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Synergistic Effects of d-Chiro-Inositol and Manganese on Blood Glucose and Body Weight of Streptozotocin-Induced Diabetic Rats


Abstract and Figures

d-chiro-inositol (DCI) and manganese were administered orally singly and together to streptozotocin (STZ)- induced diabetic rats for 21 days and blood glucose values and body weights determined. At blood glucose values above 500 mg/dL, values were unchanged with DCI, manganese sulfate, or both over ten days. Insulin was administered to reduce the hyperglycemia to approximately 300 mg/dL. Over 12 days, DCI alone significantly reduced blood glucose (23%), and the combination of DCI and manganese sulfate reduced hyperglycemia even more effectively (40%) as compared to control animals. Of further interest, body weights both of female and male rats administered DCI and manganese were reduced, with females 25% compared to controls and males 21% compared to controls over the 21-day period. Metabolic mechanisms of actions of DCI and manganese to explain these results are discussed.
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90 Current Bioactive Compounds 2010, 6, 90-96
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Synergistic Effects of d-Chiro-Inositol and Manganese on Blood Glucose
and Body Weight of Streptozotocin-Induced Diabetic Rats
Gilbert Gluck1, Tatiana Anguelova1, Douglas Heimark2 and Joseph Larner*,2
1Cyvex Nutrition, Inc., California 92614, USA
2Allomed Pharmaceuticals, Virginia 22903, USA and Department of Pharmacology, University of Virginia,
Charlottesville, VA 22908, USA
Abstract: d-chiro-inositol (DCI) and manganese were administered orally singly and together to streptozotocin (STZ)-
induced diabetic rats for 21 days and blood glucose values and body weights determined. At blood glucose values above
500 mg/dL, values were unchanged with DCI, manganese sulfate, or both over ten days. Insulin was administered to
reduce the hyperglycemia to approximately 300 mg/dL. Over 12 days, DCI alone significantly reduced blood glucose
(23%), and the combination of DCI and manganese sulfate reduced hyperglycemia even more effectively (40%) as
compared to control animals. Of further interest, body weights both of female and male rats administered DCI and
manganese were reduced, with females 25% compared to controls and males 21% compared to controls over the 21-day
period. Metabolic mechanisms of actions of DCI and manganese to explain these results are discussed.
Keywords: d-chiro-inositol, chronic administration, type 2 diabetes, hyperglycemia, manganese.
DCI and manganese have each been independently
identified as lowering elevated blood glucose in subjects
with type 2 diabetes [1,2]. In India, based on native folklore,
DCI as 1d-3-O-methyl-chiro-inositol (pinitol) was isolated
from bougainvillea leaves and shown to reduce hypergly-
cemia in STZ-induced diabetic mice [1]. In South Africa,
native alfalfa plant extracts used to treat diabetes were
examined and manganese identified as the active agent.
Administration of manganese itself reduced hyperglycemia
in diabetic subjects [2]. Further data has now shown that
both DCI and manganese are deficient in human type 2
diabetics [3-6].
We previously demonstrated that a single dose of DCI
administered intragastrically to STZ-induced type 2 model
diabetic rats and to normal rats administered an intra-
peritoneal injection of glucose lowered their elevated blood
glucose concentrations acutely within a period of 120 min
[7]. The diabetic animals had initial blood glucose values of
406 mg/dL, thus a model of type 2 diabetes, since the STZ
had only partially destroyed the pancreatic beta cells. In a
further study, an intravenous single dose of DCI in com-
bination with an intravenous infusion of manganese chloride
for 120 min produced a more pronounced effect on lowering
blood glucose in STZ-induced type 2 model diabetic rats
than DCI alone [8]. Manganese alone was without effect.
Again the initial blood glucose values of the diabetic rats
was 251 mg/dL indicating a partial destruction of the
pancreatic beta cells and a type 2 model of diabetes.
*Address correspondence to this author at the Department of Pharmacology,
1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA; Tel: (434)
924-2321; Fax: (434) 924-5207; E-mail:
This study was financed in whole by Cyvex Nutrition, Inc. Irvine, CA
The purpose of the present study was to investigate the
possible effect of chronic oral administration of Chirositol,
95% DCI alone (Cyvex Nutrition, Inc.) and in combination
with manganese sulfate on reducing elevated blood glucose
in STZ-induced Sprague-Dawley diabetic rats.
Sprague-Dawley rats, 8 weeks old of both sexes weigh-
ing 180-260 g were injected with STZ (50 mg/kg, i.p.). After
72 h, blood glucose was sampled from the tail vein and
plasma glucose was measured with ACCU-CHEK®- softclix
plus kit. Diabetes was established with blood glucose values
greater than 500 mg/dL modeling type 1 diabetes. Blood
samples were collected once a day in the morning during the
whole study. Animals had access to water and food ad
libitum and were fed HARLAN-T7012.15 diet. Light was
switched on/off at 12 h intervals. Body weight of the animals
was measured every morning.
Phase I Study
Initially, four groups of animals were administered either
DCI, manganese, both DCI and manganese sulfate, or saline.
Group 1 (n=8) was administered Chirositol (20 mg/kg in
0.9 % w/v of NaCl, saline solution); administration by oral
gavage twice a day (at 8 h intervals). Group 2 animals (n=8)
received 3.3 mg/kg manganese sulfate (Jost Chemicals);
Group 3 animals (n=8) received 20 mg/kg Chirositol and
3.3 mg/kg manganese sulfate; Group 4 animals (n=8)
received saline solution (control group).
Phase II Study
Insulin was next administered to all animals to partially
decrease but still maintain hyperglycemic blood glucose
values. All animals were administered 2 units (72 mcg)
insulin per day (Lantus insulin from Sanofi-aventis) injected
Synergistic Effects of d-Chiro-Inositol and Manganese Current Bioactive Compounds 2010, Vol. 6, No. 2 91
subcutaneously post gavage. Insulin treatment reduced basal
blood glucose values to about 400 mg/dL. Animals in Group
1 (n=15) received Chirositol 95% d-chiro-Inositol (20
mg/kg in 0.9 % w/v of NaCl, saline solution); Group 2
(n=21) received 20 mg/kg Chirositol and 3.3 mg/kg
manganese sulfate; Group 3 (control group, n=6) received
saline solution only; administration by oral gavage twice a
day (at 8 h interval).
Values are presented as mean ± SEM. Group mean diffe-
rences were compared by ANOVA followed by Bonferroni
and Newman-Keuls Multiple Comparison tests. Differences
with p<0.05 were considered significant.
No significant changes in the blood glucose levels were
observed with any of the administered agents during the ten
days of Phase I study. Initial injection of streptozotocin had
destroyed sufficient islet beta cells inducing a model of type
1 diabetes with blood glucose values of 600 mg/dL and
higher (Fig. 1).
Since our previous studies with DCI and manganese were
done with STZ-induced diabetic rats with blood glucose
values in the range of 250-400 mg/dL, closer to a model of
type 2 diabetes [7,8] we injected insulin to lower blood
glucose values to 300-400 mg/dL to more closely model our
previous conditions.
Insulin administration for 3 days, 10-12, during the Phase
II study reduced blood glucose levels of all animals to 400
mg/dL (Fig. 2). Blood glucose levels of the saline control
group were not further reduced by insulin administration for
the remaining nine days of the study and on day 21, blood
glucose values remained in the 400 mg/dL range. In contrast,
DCI alone administered for the remaining nine days at a
bolus dose of 20 mg/kg twice a day (Group 1) further
decreased blood glucose by 23%, which on day 21 was
significantly different from the control saline group (p<0.03)
(Figs. 2 and 3). Administration of 20 mg/kg DCI in combi-
nation with 3.3 mg/kg manganese sulfate twice a day
resulted in a 40% decrease in plasma glucose (Group 2),
which on day 21 was significantly different from the saline
(control) group (p<0.0001). This antihyperglycemic effect of
the combination of DCI and manganese sulfate on day 21
was also significantly different from that produced by DCI
alone (p<0.008) (Figs. 2 and 3).
Fig. (1). Mean blood glucose, male and female rats combined, for experiment modeling type 1 diabetes. Values are expressed as mean ±
SEM. A: control rats (n = 8); B: rats administered DCI alone (n = 8); C: rats administered Mn2+ alone (n = 8); D: rats administered DCI +
Mn2+ (n = 8). D1 POST, D2 POST and D3 POST denotes day 1, 2 and 3 post-STZ administration.
92 Current Bioactive Compounds 2010, Vol. 6, No. 2 Gluck et al.
Fig. (2). Mean blood glucose ± SEM, for both male and female rats,
for Phase 2 study. Group 1: DCI, n=15; Group 2: DCI + Mn2+,
n=21; Group 3: Control (0.9% NaCl), n=6. All animals received 2
units insulin per day.
Fig. (3). Mean blood glucose on days 19 to 21 for both male and
female rats. Glucose values for DCI, DCI + Mn2+ and control are
plotted. Values are expressed as mean ± SEM with p values above
each significant pair.
The rate of decrease in plasma glucose of Group 2 (DCI
+ MnSO4) was also more pronounced than that of Group 1
(DCI) (Fig. 4). Linear regression slopes of blood glucose
Fig. (4). Mean rate of decline of blood glucose of combined male
and female rats for days 17 to 21. Rats are administered either DCI
alone (n=15) or DCI + Mn2+ (n=21). The two regression slopes are
statistically different (p = 0.043).
decrease during days 17 to 21 were respectively -9 for DCI
(p=0.0362) and -16 for the combination of DCI and
manganese sulfate (p=0.0013). The two regression lines are
significantly different from each other (p = 0.043).
When body weights were measured, female rats of both
Group 1 (DCI, n=8) and Group 2 (DCI + MnSO4, n=12)
unexpectedly demonstrated a 35% net loss of weight as
compared to controls, (n=3) (Fig. 5A). Control male and
female rats gained body weight during the experimental
period. The weight loss for the female rats became
statistically significant starting on day 13 (p = 0.03 DCI vs.
control; p = 0.048 DCI + MnSO4 vs. control). The p values
progressively decreased and on day 21 were p = 0.0033 and
p = 0.006 respectively for DCI vs. control and DCI + MnSO4
vs. control. When body weights of males were measured
(Fig. 5B) DCI (n=8) and DCI+MnSO4 (n=12) also
demonstrated a net loss of weight compared to control males
(n=4) but did not decrease to the same extent as did females.
The Group 1 and Group 2 slopes for the female rats’ weight
loss was statistically different from those of the Group 1 and
Group 2 male rats (p<0.001). Differences in weight became
statistically significant for the male rats on day 10 for DCI
(p=0.0057); DCI + Mn2+ (p=0.026). Except for day 12, the
significance for male weight loss progressively lowered to
p<0.001 on day 21 for both DCI and DCI + Mn2+. Fig. (6), in
table format, summarizes the blood glucose values and body
Fig. (5). Female (A) and male (B) rat body weights measured
initially at day 0 and then daily from days 10 to 21. Rats are
administered DCI alone or DCI + Mn2+. Values are normalized
against control and expressed as % control ± SEM. A: The weight
loss becomes statistically significant in female rats starting on day
13 (p = 0.03 DCI vs. control; p = 0.048 DCI + Mn2+ vs. control) and
progressively lower p values until day 21 (p = 0.0033 DCI vs.
Control; p = 0.006 DCI + Mn2+ vs. control). B: The weight loss in
males becomes statistically significant starting on day 10 (p =
0.0057 DCI vs. Control; p = 0.0259 DCI + Mn2+ vs. control) and
progressively lower p values until day 21 (p < 0.001 DCI vs. control
and DCI + Mn2+ vs. control).
Synergistic Effects of d-Chiro-Inositol and Manganese Current Bioactive Compounds 2010, Vol. 6, No. 2 93
In a previous report, we observed an acute additive effect
of a single bolus dose of DCI and an infusion of MnCl2 for
120 min to further reduce hyperglycemia in STZ type 2
model diabetic rats (plasma glucose 251 ± 7 mg/dL) above
that of DCI alone [8]. Manganese alone was ineffective in
that experiment. In the present Phase I experiment, chronic
oral 10-day administration of DCI and manganese sulfate
alone and in combination was ineffective in decreasing high
blood glucose values of 600 mg/dL. Since previous expe-
riments had been done with diabetic animals with initial
blood glucoses in the 250-400 mg/dL range, we injected
insulin to lower initial blood glucose values from 600 mg/dL
to 400 mg/dL. This was termed Phase II. In the Phase II
experiment, we examined the effect of chronic oral adminis-
tration of DCI alone versus administration of DCI with
manganese sulfate in STZ-induced diabetic rats with
decreased initial blood glucose values. Under these condi-
tions, with adequate insulin present, the antihyperglycemic
effect of DCI was significantly further enhanced by the
addition of manganese sulfate.
The early folk medicine literature clearly demonstrates
the antihyperglycemic effects of Mn2+ in diabetic humans [2]
and of DCI as pinitol in diabetic mice [1]. More recent
literature clearly demonstrates the antihyperglycemic effec-
tiveness of DCI in type 2 diabetic rats [7], monkeys [9] and
human subjects with metabolic syndrome [10], type 2 dia-
betes [11-13] and with polycystic ovarian syndrome (PCOS)
associated with insulin resistance [14].
More specifically, we gavaged DCI (1-10 mg/kg) into
STZ-induced diabetic rats and demonstrated a dose-
dependent reduction of hyperglycemia of up to 40% [7],
Bates et al., administered pinitol (5-100 mg/kg) orally to
STZ-induced diabetic rats, and reported that it lowered
hyperglycemia in a dose-dependent manner over a 6-hour
period [15]. Pinitol and/or DCI (10 mg/kg/day) were
administered chronically (for 12 weeks) to STZ-induced
diabetic mice. Both inositols normalized hyperglycemia to
euglycemia in 6 weeks [16].
In hyperinsulinemic insulin-resistant monkeys, intrave-
nous (IV) administration of a single dose of DCI (100
mg/kg) significantly increased the rates of disappearance of
blood glucose by 129 ± 4 mg/dl [7] and of insulin by 89 ±
39%, while oral administration of DCI (500 mg/kg) with a
meal to these hyperinsulinemic insulin-resistant monkeys
decreased blood glucose and insulin compared with control
monkeys [7]. DCI (1000 mg/kg) was administered IV to
insulin-resistant and diabetic monkeys in the presence of
insulin under steady-state clamp conditions, and muscle
biopsy samples were assayed for GS activity. GS fractional
velocity was significantly increased (25 ± 6%) compared
with insulin alone, demonstrating an insulin-sensitizing
action [17].
In mild type 2 diabetics (n=57), DCI was administered
orally (1200 mg/day) for 28 days; metabolic parameters were
compared with diabetic individuals who were not adminis-
tered DCI. Those individuals who had received DCI showed
statistically significant decreases in diastolic blood pressure,
triglycerides, cholesterol and low-density lipoprotein (LDL)
cholesterol. There was a 49 mg/dL decrease in blood glucose
in the 2-hr oral glucose tolerance test (OGTT) and a 9.2 %
reduction in the OGTT blood glucose area under the curve
(AUC). Thus, administration of DCI improves aspects of the
metabolic syndrome. Surprisingly, a significant reduction in
HbA1c was observed after 28 days, much earlier than seen in
other clinical trials with anti-diabetic therapy [10]. DCI was
administered orally (1200 mg/day) for 6 to 8 weeks to 22
DCI DCI + Mn2+ Control
DCI DCI + Mn2+ Control
DCI DCI + Mn2+ Control
Day n = 15 n = 21 n = 6
n = 8 n = 12 n = 4
n = 8 n = 12 n = 3
244 ± 3 247 ± 2 251 ± 4
230 ± 4 204 ± 3 207 ± 6
10 599 ± 1 594 ± 4 598 ± 2
287 ± 2 302 ± 6 336 ± 12
187 ± 6 189 ± 7 198 ± 5
11 487 ± 21 474 ± 20 409 ± 37
12 398 ± 32 369 ± 24 368 ± 29
300 ± 15 302 ± 6 340 ± 12
188 ± 7 190 ± 7 220 ± 6
13 452 ± 31 472 ± 18 421 ± 32
287 ± 8 301 ± 6 342 ± 12
188 ± 6 188 ± 7 224 ± 7
14 392 ± 36 394 ± 20 434 ± 25
288 ± 8 296 ± 8 344 ± 12
190 ± 6 189 ± 7 226 ± 7
15 402 ± 29 383 ± 30 441 ± 39
286 ± 8 301 ± 6 350 ± 12
187 ± 6 187 ± 7 228 ± 7
16 395 ± 38 376 ± 29 374 ± 54
283 ± 8 300 ± 6 351 ± 12
185 ± 7 186 ± 7 228 ± 7
17 357 ± 34 314 ± 25 397 ± 44
282 ± 8 298 ± 6 352 ± 12
183± 6 184 ± 7 230 ± 7
18 359 ± 32 306 ± 21 430 ± 38
281 ± 8 297 ± 6 352 ± 13
182 ± 7 183 ± 7 232 ± 7
19 355 ± 29 280 ± 18 429 ± 34
278 ± 8 295 ± 6 354 ± 12
180 ± 7 181 ± 7 232 ± 6
20 331 ± 29 267 ± 18 413 ± 29
277 ± 8 293 ± 6 355 ± 12
179 ± 6 180 ± 7 233 ± 6
21 326 ± 24 252 ± 15 424 ± 29
275 ± 8 292 ± 6 356 ± 13
177 ± 6 178 ± 7 235 ± 7
Fig. (6). Summary of blood glucose and body weights. Glucose and body weights measured initially (day 0) and from day 10 to day 21.
Values are means ± SEM. Blood glucose for male and female are pooled and averaged.
94 Current Bioactive Compounds 2010, Vol. 6, No. 2 Gluck et al.
women with PCOS, and their metabolic parameters were
compared with those of control women with PCOS who
were not administered DCI. Administration of DCI increased
insulin action, improved ovulatory function, and decreased
serum androgen concentrations, blood pressure and serum
triglycerides [14].
Three clinical trials have been conducted in South Korea
to investigate administration of pinitol to individuals with
type 2 diabetes. In the first trial, 33 individuals with type 2
diabetes were administered 1200 mg pinitol/day for 13
weeks and compared with control diabetic individuals who
were administered placebo. This treatment regimen reduced
fasting blood glucose levels (157 ± 22 vs. 127 ± 77 mg/dL),
whereas no changes were observed in the group administered
placebo (158 ± 20 vs. 157 ± 17 mg/dL). In addition, the
levels of HbA1c decreased significantly in the group
administered pinitol (8.9 ± 1.1% vs. 7.8 ± 0.9%) compared
with the control group (8.8 ± 1.4% vs. 8.8 ± 1.4%) [11].
Similar reductions were observed in second trial in which 20
type 2 diabetics were administered 20 mg/kg/day pinitol for
12 weeks. Fasting blood glucose decreased significantly in
the group administered pinitol (200 ± 38 vs. 169 ± 50
mg/dL), as did HbA1c (9.8 ± 1.6% vs. 8.3 ± 1.1%) [12].
Finally, the third trial was a double-blind study in which 82
type 2 diabetics were randomized to receive pinitol (400 mg)
or placebo three times a day for 12 weeks. Again, fasting
blood glucose decreased significantly in the pinitol group
(184 ± 104 vs. 129 ± 47 mg/dL) but not in the placebo group
(173 ± 64 vs. 168 ± 67 mg/dL), as did HbA1c (Pinitol: 8.4 ±
1.6% vs. 7.8 ± 1.5%; Placebo: 8.4 ± 1.2% vs. 8.5 ± 1.3%)
[13]. Thus there is accumulated evidence for the effec-
tiveness of DCI and pinitol to ameliorate hyperglycemia and
restore metabolic balance in insulin resistance states.
In the body tissues, chiro-inositol is present linked to
amino sugars as chiro-inositol glycans. These glycans have
insulin-mimetic and insulin-sensitizing properties and have
been termed insulin second messengers or mediator-
modulators (see below). The literature clearly demonstrates
about a 50% decrease of chiro-inositol-glycan mediator bio-
activity and chiro-inositol content in urine, hemodialysate
and muscle of type 2 diabetic subjects compared to controls
[4]. In muscle biopsy studies strikingly, no chiro-inositol
was detected in chiro-inositol mediator preparations from
type 2 diabetic subjects before or after insulin adminis-
tration. Myo-inositol glycan was present and clearly inc-
reased after insulin administration [3]. By contrast, in control
healthy subjects chiro-inositol glycan and myo-inositol
glycan were present before insulin and increased after insulin
administration [3]. A deficit of chiro-inositol in urine in type
2 diabetic subjects has been correlated with severity of
insulin resistance [18]. With regard to manganese, there are a
number of conflicting reports comparing the contents in
diabetic and control urine and blood cells [5,6,19-21].
However, analyses of hair and scalp specimens reveal lower
levels in human type 2 diabetics than normals [5]. In animal
studies, a manganese deficient diet clearly results in
impaired glucose tolerance and the generation of reactive
oxygen species with resultant islet beta cell damage related
to manganese superoxide dismutase deficiency [22-24].
Therefore, replacement therapy with both agents appears
both reasonable and logical.
Considering replacement therapy, DCI administration has
been shown to have two beneficial effects. First, DCI itself
has beneficial antioxidant properties [25]. It prevents oxida-
tive damage by reducing reactive oxygen species formation
in endothelial cells exposed to high glucose, protects the
vascular endothelium and allows it to produce nitric oxide to
dilate blood vessels, a normal function of insulin [26]. By
protecting NO, DCI prevents the loss of and restores
endothelial function.
Second, in the body DCI is converted into DCI-glycan
precursor phospholipids [26], from which DCI-glycan me-
diators are released by insulin [27]. Decreased chiro-inositol
glycan release by insulin in blood has been observed in
human type 2 diabetes [28], in blood of women with
polycystic ovarian syndrome with insulin resistance [29],
and in placental membranes from women with preeclampsia
associated with insulin resistance [30]. Thus DCI is effective
alone as an antioxidant and as a chiro-inositol glycan to
restore metabolic intracellular glucose disposal.
What is the mechanism of action of DCI-glycan media-
tors and of manganese? We isolated from beef liver the first
example of a DCI-glycan mediator. It was chelated to man-
ganese [31]. It has insulin-mimetic and sensitizing
properties. We determined its structure as pinitol linked -
1,4 to galactosamine chelated to manganese. It has been
chemically synthesized as 2-amino-2-deoxy--d-galacto-
pyranosyl-(1,3)-1d-4-O-methyl-chiro-inositol and named
INS-2. INS-2 allosterically activates two key phosphoprotein
phosphatases, PP2C which dephosphorylates and activates
glycogen synthase (GS) and mitochondrial PDHP, which
dephosphorylates and activates pyruvate dehydrogenase
(PDH). Thus, INS-2 mimics two classical actions of insulin.
These two rate-limiting enzymes (GS and PDH) activate
intracellular glucose disposal via glycogen synthesis and
mitochondrial pyruvate oxidation and generation of ATP
Manganese is an important element not only in the
structure of chiro-inositol glycans, but also in the structure
and function of PP2C and PDHP. Both phosphatases are
members of the same PPM family with 20-25% amino acid
identity and both require manganese or magnesium for
bioactivity. Their X-ray crystal structures demonstrate that
both have bimetallic (Mn2+ or Mg2+) centers as elements of
their catalytic sites [33,34].
Thus, DCI and manganese are combined in vivo in the
cell in the form of chelated insulin mediator glycans such as
INS-2. In addition, both phosphoprotein phosphatases PP2C
and PDHP, which activate glycogen synthesis and pyruvate
oxidation, require manganese and/or magnesium for bioac-
tivity. By these mechanisms both DCI and manganese act to
restore normal physiological balance and their prolonged
combined supplementation demonstrates an enhanced
antihyperglycemic effect as compared to DCI alone.
No significant changes in plasma glucose values were
observed with any administered agent during the Phase I
study where STZ had destroyed sufficient islet beta cells to
produce a model of type 1 diabetes with glucose values of
600 mg/dL. In a previous short term acute experiment in
severely diabetic STZ-induced rats, a model of type 1
diabetes, with initial blood glucose values of 500-600 mg/dL
Synergistic Effects of d-Chiro-Inositol and Manganese Current Bioactive Compounds 2010, Vol. 6, No. 2 95
[32], we demonstrated that insulin alone was ineffective in
decreasing elevated blood glucose without the prior adminis-
tration of the DCI-glycan INS-2. When INS-2 was first
injected, then insulin was effective. This suggested that for
insulin to act there had to be available a tissue pool of DCI-
glycan to act as an intracellular mediator. Thus under these
conditions, INS-2 was acting in the presence of an ineffec-
tive insulin concentration as an insulin sensitizer. We
therefore in Phase II administered insulin to lower plasma
glucose values to about 300-400 mg/dL. Our hypothesis is
that in this chronic experiment, this administered insulin
resulted in the replacement of the inositol glycan precursor
phospholipid pool by the orally administered DCI and
manganese. We have previously shown that insulin stimu-
lates the incorporation of [3H]myo-inositol into [3H]chiro-
inositol precursor phospholipids in fibroblasts [26]. Thus
insulin acts both to generate the inositol glycan phospholipid
pool and to stimulate the release of the inositol glycan from
the precursor phospholipid. Both are defective in the absence
of insulin.
In the present experiment supplementation of DCI and
manganese sulfate prevented weight gain in male rats and
decreased body weight of female rats. The mechanism of
action will require further investigation, as well as the diffe-
rence between male and female weight response. However, it
is possible to speculate that insulin action in the hypotha-
lamus as an antiorexigenic agent may in part be related to the
generation of inositol-glycans, such as INS-2, which mimic
the action of insulin in the CNS.
This study was financed in whole by Cyvex Nutrition,
Inc. Irvine, CA 92614.
DCI = d-chiro-inositol
GS = Glycogen synthase
Pinitol = 1d-3-O-methyl-chiro-inositol
INS-2 = 2-amino-2-deoxy--d-galactopyranosyl-(1,3)-
PDH = Pyruvate dehydrogenase
STZ = Streptozotocin
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Received: August 24, 2009 Revised: January 20, 2010 Accepted: February 03, 2010
... Moreover, in some insulin resistance conditions, a defect of myoinositol epimerization to DCI was observed, resulting to an ''inositol imbalance'' with higher myo-inositol and lowest DCI levels in insulin-sensitive tissues compared to healthy subjects [7,8]. Accordingly, in animal models and in T2D patients, a reduction in DCI plasma levels with a decreased DCI urinary excretion related to the different degree of insulin resistance was reported [9,10]. On this basis, inositol oral administration could play an important role in insulin resistance pathogenesis, avoiding the faulty epimerase and improving peripheral insulin sensitivity as shown in vivo and in the experimental studies [11][12][13]. ...
... Consequently, in some insulin resistance conditions such as polycystic ovary syndrome (PCOS), the efficacy of DCI oral supplementation has been widely demonstrated [17]. In insulin-resistant women with PCOS, DCI is effective in improving ovulatory function, metabolic parameters and serum androgen concentration [17][18][19][20][21]. Similarly, Gluck et al. [10] have demonstrated the DCI putative effect on glucose homeostasis and insulin sensitivity in streptozotocin (STZ)-induced diabetic rats. Accordingly, clinical studies showed an improvement of glycaemic control with a reduction in fasting blood glucose and decreased HbA1c levels in T2D patients [22,23]. ...
Aims: To improve insulin sensitivity, insulin-sensitizing drugs such as metformin are commonly used in overweight and obese T1D patients. Similarly to metformin, D-chiro-inositol (DCI), as putative mediator of intracellular insulin action, can act as insulin sensitizer. The aim of this pilot study was to evaluate the hypothesis that DCI plus folic acid may improve glucose control reducing insulin resistance in overweight or obese T1D patients. Methods: A 24-week randomized control trial was carried out in 26 overweight or obese T1D patients, undergoing intensive insulin therapy. Patients were randomized to 1 g DCI plus 400 mcg folic acid once daily (treated group) or to 400 mcg folic acid only once daily (control group). The primary end point was to evaluate the efficacy of DCI on metabolic control as assessed by HbA1c. As secondary endpoints, BMI and insulin requirement (IR) were evaluated. Paired t test (two tailed) and analysis of variance were used to evaluate differences in HbA1c, BMI and IR at different time points. Results: A significant reduction in HbA1c levels in treated group versus control group (7.5% ± 0.9 vs. 7.9% ± 1.7, respectively, p < 0.05) was observed. However, no significant reduction in BMI and IR was observed [(BMI 25.7 ± 2.8 vs. 26.7 ± 1.0, respectively, p NS); (IR 0.52 ± 0.26 vs. 0.52 ± 0.19, respectively, p NS)]. Conclusions: This trial demonstrated for the first time that DCI plus folic acid oral supplementation can improve metabolic control in overweight T1D patients. CLINICALTRIAL. Gov id: NCT02730949.
... марганец: на 25% у самок и на 21% у самцов по сравнению с контролем в течение 21 дня [30]. ...
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D-chiroinositol (DCI) is one of the 9 inositol isomers that forms inositol phosphoglycans, which are mediators of the action of insulin. The metabolism of DCI and myo-inositol (MI) is impaired against the background of insulin resistance, including the patients with polycystic ovary syndrome (PCOS). Aim. Highlight the most characteristic pharmacological properties of DCI. Materials and methods. Systematic computer analysis of 45 600 publications on the biological roles of inositol by methods of the topological theory of pattern recognition and systems biology analysis of human proteome. Results. A complex of interactions between metabolic disorders of DCI, PCOS, ovulation disorders, obesity associated with numerous hormonal disorders is described. Supplements with DCI and MI increase the sensitivity of cells to insulin and normalize the metabolism of androgens. An important difference between DCI and MI is the presence of DCI in the composition of inositol phosphoglycans that mediate the action of insulin on cells, as well as its participation in the realization of the therapeutic effects of metformin. The use of the MI+DCI combination allows achieving positive dynamics in reducing excess body weight, normalizing blood lipids, glucose and insulin levels, restoring the ovulatory menstrual cycle, improving oocyte quality, and helps prevent gestational diabetes in pregnant women and macrosomia of the fetus. DCI is more effective than MI in reducing the risk of folate-resistant neural tube defects. Conclusion. The therapeutic potential of DCI in combination with MI for treating PCOS and hyperandrogenism is evident. Depending on the therapeutic expediency, various ratios of MI:DCI can be used for the treatment of PCOS and disorders of carbohydrate and lipid metabolism.A
... Gluck et al. [71] observed that d-chiro-inositol (DCI) and manganese sulfate reduced hyperglycemia even more effectively (40%) as compared to control animals. They suggested that DCI and manganese are combined in vivo in the cell in the form of chelated insulin mediator glycans such as INS-2. ...
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Diabetes mellitus (DM) represents one of the greatest threats to modern global health. Diabetes mellitus is characterized by chronic elevation of blood glucose concentration as a consequence of decreased blood insulin levels or decreased action of insulin. In order to prevent or delay the onset of such complications, tight control of fasting and postprandial blood glucose levels is a central aspect of diabetes treatment. Development of new therapies that are able to improve glycemia management, cure diabetes, and can even protect from it, are of great interest. Metal compounds proposed to have the potential to elicit beneficial effect in the pathogenesis and complication of the disease. The idea of using metal ions for the treatment of diabetes originates from the report in 1899. Vanadium, chromium, copper, cobalt, tungsten and zinc were found to be effective for treating diabetes in experimental animals. Results from long-term trials are needed in order to assess the safety and beneficial role of these metals as complementary therapies in the management of diabetes. The present review includes the therapeutic potential of some metals showing promising result in the treatment of diabetes.
... We did not measure blood insulin levels in the present study and this is a limitation. Gluck et al. [19] have also recently reported that for STZinduced diabetic rats with very high glucose levels (<500 mg/dl), administered DCI had no hypoglycaemic effect. They further showed that DCI produced a hypoglycaemic effect only when the glycaemia was first reduced to about 300 mg/dl by the prior injection of a small dose of insulin. ...
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D-chiro-inositol (DCI) has been shown to prevent and reverse endothelial dysfunction in diabetic rats and rabbits. The present study evaluates the preventive effect of DCI on experimental diabetic neuropathy (DN). Streptozotocin-induced (STZ) diabetic mice were treated by oral gavage for 60 days with DCI (20 mg/kg/12 h) or saline (NaCl 0.9%; 0.1 ml/10 g/12 h; Diab) and compared with euglycaemic groups treated with saline (0.1 ml/10 g/12 h; Eugly). We compared the response of the isolated sciatic nerve, corpora cavernosa or vas deferens to electrical stimulation. The electrically evoked compound action potential of the sciatic nerve was greatly blunted by diabetes. The peak-to-peak amplitude (PPA) was decreased from 3.24 ± 0.7 to 0.9 ± 0.2 mV (p < 0.05), the conduction velocity (CV) of the first component was reduced from 46.78 ± 4.5 to 26.69 ± 3.8 ms (p < 0.05) and chronaxy was increased from 60.43 ± 1.9 to 69.67 ± 1.4 ms (p < 0.05). These parameters were improved in nerves from DCI-treated mice (p < 0.05). PPA in the DCI group was 5.79 ± 0.8 mV (vs. 0.9 ± 0.2 mV-Diab; p < 0.05) and CV was 45.91 ± 3.6 ms (vs. 26.69 ± 3.8 ms-Diab; p < 0.05). Maximal relaxation of the corpus cavernosum evoked by electrical stimulation (2-64 Hz) in the Diab group was 36.4 ± 3.8% compared to 65.4 ± 2.8% in Eugly and 59.3 ± 5.5% in the DCI group (p < 0.05). Maximal contraction obtained in the vas deferens was 38.0 ± 9.2% in Eugly and 11.5 ± 2.6% in Diab (decrease of 69.7%; p < 0.05), compared to 25.2 ± 2.3% in the DCI group (p < 0.05 vs. diabetic). Electron microscopy of the sciatic nerves showed prevention of neuronal damage. DCI has a neuroprotective action in both autonomic and somatic nerves in STZ-induced DN.
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The purpose of this study was to determine whether the treatment with recombinant plasmid consisted of human GLP1 promoter and insulin gene can treat diabetic rats. Rats were induced type-1 diabetes mellitus (T1DM) by a single dose of intraperitoneal injection of streptozotocin (STZ) at dose of 55mg/kg. The induction of diabetes was confirmed in rats by checking the blood glucose level for seven days. The recombinant plasmid, GLP1/Ins/pBud plasmid, was wrapped with chitosan and then transferred to diabetic rats by force feeding. The blood glucose level was checked from the tips of the tails by needle puncture using a glucometer and test strips. The blood levels of human and rat insulin were assessed by enzyme-linked immunosorbent assay (ELISA). The results showed no significant effects of orally treatment with recombinant plasmid DNA at both doses of 100 and 600 µg/mL on the human insulin level in diabetic rats (p>0.05). The human insulin level was significantly increased by orally treatment at dose of 300 µg/mL (p=0.04). The findings indicated that the intraperitoneal injection of 300 µg/mL of this nanoparticle complex prominently increased the human insulin level in diabetic rats in contrast to both doses of 100 and 600 µg/mL. Despite above results, both methods was not effective enough to decrease the blood glucose levels in diabetic rats. It was concluded that the treatment of diabetic rats with recombinant plasmid consisted of human GLP1 promoter and insulin gene was not effective to reduce the blood glucose levels in diabetic rats. © 2017 Association of Biotechnology and Pharmacy. All Rights Reserved.
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Type II diabetic Goto-Kakizaki (GK) rats were insulin-resistant in euglycemic-hyperinsulinemic clamp studies. We therefore examined insulin signaling systems in control Wistar and diabetic GK rats. Glycerol-3-phosphate acyltransferase (G3PAT), which is activated by headgroup mediators released from glycosyl-phosphatidylinositol (GPI), was activated by insulin in intact and cell-free adipocyte preparations of control, but not diabetic, rats. A specific chiro-inositol-containing inositol phosphoglycan (IPG) mediator, prepared from beef liver, bypassed this defect and comparably activated G3PAT in cell-free adipocyte preparations of both diabetic GK and control rats. A myo-inositol-containing IPG mediator did not activate G3PAT. Relative to control adipocytes, labeling of GPI by [^3H]glucosamine was diminished by 50% and insulin failed to stimulate GPI hydrolysis in GK adipocytes. In contrast to GPI-dependent G3PAT activation, insulin-stimulated hexose transport was intact in adipocytes and soleus and gastrocnemius muscles of the GK rat, as was insulin-induced activation of mitogen-activated protein kinase and protein kinase C. We conclude that (i) chiro-inositol-containing IPG mediator activates G3PAT during insulin action, (ii) diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing IPG, and (iii) defective IPG-regulated intracellular glucose metabolism contributes importantly to insulin resistance in diabetic GK rats.
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To assess the effects of soybean-derived pinitol on glycaemic control and cardiovascular risk factors in Korean patients with type II diabetes mellitus. Randomized, double-blind, placebo-controlled, parallel-group trial. Pusan Paik Hospital, Pusan, Republic of Korea. A total of 30 patients with type II diabetes received an oral dose of 600 mg soybean-derived pinitol or placebo twice daily for 13 weeks. Pinitol significantly decreased mean fasting plasma glucose, insulin, fructosamine, HbA1c, and the homeostatic model assessment insulin resistance index (HOMA-IR, P<0.001). Pinitol significantly decreased total cholesterol, LDL-cholesterol, the LDL/HDL-cholesterol ratio, and systolic and diastolic blood pressure and increased HDL-cholesterol (P<0.05). These data suggest that soybean-derived pinitol may be beneficial in reducing cardiovascular risk in Korean type II diabetes.
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To evaluate copper, zinc, manganese, magnesium, and other indices of peroxidative status in diabetic and nondiabetic human subjects. Convenience sample of 57 insulin-dependent or non-insulin-dependent diabetic subjects recruited from the diabetes clinic of the University of California, Davis, Medical Center and 28 nondiabetic subjects recruited from the staffs of the Departments of Internal Medicine and Nutrition. Individuals conducting laboratory analyses were blind to subject group. A fasting blood sample was collected from all subjects and appropriately processed for future analyses. A 24-h urine collection was obtained in a subset of subjects. Hyperzincuria and hypermagnesuria were evident in diabetic subjects compared with control subjects. There were no differences in plasma magnesium or whole-blood manganese between groups. Plasma copper was higher and plasma zinc was lower in diabetic than in control subjects. When data were viewed with respect to specific diabetes-associated complications, diabetic subjects with retinopathy, hypertension, or microvascular disease had higher plasma copper concentrations compared with both diabetic subjects without complications and with control subjects. There were no significant differences between control and diabetic subjects in erythrocyte copper-zinc superoxide dismutase activity or whole-blood glutathione peroxidase or glutathione reductase activities. Plasma peroxide concentrations were higher in diabetic than control subjects. Diabetes can alter copper, zinc, magnesium, and lipid peroxidation status. Perturbations in mineral metabolism are more pronounced in diabetic populations with specific complications. It is not known whether differences in trace element status are a consequence of diabetes, or alternatively, whether they contribute to the expression of the disease.
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BACKGROUND and Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM: The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined. The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM: Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM: NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM:
Protein phosphatase 2C (PP2C) is a Mn2+‐ or Mg2+‐dependent protein Ser/Thr phosphatase that is essential for regulating cellular stress responses in eukaryotes. The crystal structure of human PP2C reveals a novel protein fold with a catalytic domain composed of a central beta‐sandwich that binds two manganese ions, which is surrounded by alpha‐helices. Mn2+‐bound water molecules at the binuclear metal centre coordinate the phosphate group of the substrate and provide a nucleophile and general acid in the dephosphorylation reaction. Our model presents a framework for understanding not only the classical Mn2+/Mg2+‐dependent protein phosphatases but also the sequence‐related domains of mitochondrial pyruvate dehydrogenase phosphatase, the Bacillus subtilus phosphatase SpoIIE and a 300‐residue domain within yeast adenyl cyclase. The protein architecture and deduced catalytic mechanism are strikingly similar to the PP1, PP2A, PP2B family of protein Ser/Thr phosphatases, with which PP2C shares no sequence similarity, suggestive of convergent evolution of protein Ser/Thr phosphatases.
Chiroinositol, a component of an inositol phosphoglycan, has been found to be reduced in the urine of humans and monkeys with non-insulin-dependent diabetes mellitus. To determine whether in vivo repletion of this inositol could improve the action of insulin on skeletal muscle glycogen synthase and glycogen phosphorylase, D-chiroinositol was administered intravenously to six monkeys during a euglycemic hyperinsulinemic clamp. Enzyme activities were determined in vastus lateralis which was freeze-clamped in situ at three time periods: immediately prior to initiation of the clamp, after steady-state glucose and insulin concentrations had been reached and the glucose disposal rate determined, and 30 min after the administration of D-chiroinositol which was superimposed on the steady-state clamp condition. D-chiroinositol increased the activity (independent and fractional velocity) of glycogen synthase (P < 0.05) and decreased the activity (independent and activity ratio) of phosphorylase (P < 0.05) compared with the samples during the clamp immediately prior to D-chiroinositol administration. Total activities of glycogen synthase and glycogen phosphorylase were not different between any of the conditions studied. We conclude that intravenous administration of D-chiroinositol enhances intracellular insulin action on muscle glycogen synthase and glycogen phosphorylase in rhesus monkeys.
PLANT extracts have long been used as home remedies for diabetes mellitus1-3, and have been investigated for their hypoglycæmic effect4,5. However, there has been little experimental or clinical proof of their efficacy6.
This study aimed to compare the trace element status of patients with type 2 diabetes (n=53) with those of nondiabetic healthy controls (n=50). The concentrations of seven trace elements were determined in the whole blood, blood plasma, erythrocytes, and lymphocytes of the study subjects. Vanadium and iron levels in lymphocytes were significantly higher in diabetic patients as compared to controls (p<0.05 for iron and p<0.01 for vanadium). In contrast, lower manganese (p<0.01) and selenium (p<0.01) concentrations were detected in lymphocytes derived from patients with type 2 diabetes versus healthy subjects. Furthermore, significantly lower chromium levels (p<0.05) were found in the plasma of diabetic individuals as compared to controls. Trace element concentrations were not dependent on the degree of glucose control as determined by correlation analysis between HBA1c versus metal levels in the four blood fractions. In summary, this study primarily demonstrated that trace element levels in lymphocytes of patients with type 2 diabetes could deviate significantly from controls, whereas, in general, no considerable differences could be found when comparing the other fractions between both patient groups. Therefore, it seems reasonable to analyze metal levels in leukocytes to determine trace element status in patients with type 2 diabetes and perhaps in other diseases.
The effects of low dietary manganese during pre- and postnatal development on glucose utilization of young adult guinea pigs is reported. Glucose tolerance tests were performed on deficient and control guinea pigs, using both oral and intravenous glucose administration. Deficient guinea pigs showed decreased utilization of glucose and in consequence had a diabetic-like glucose curve in response to glucose loading. Control animals and deficient guinea pigs, given dietary manganese equivalent in amount to that supplied control animals for 2 months, showed normal responses to glucose administration.