These studies discuss
and their effectiveness in human trials on Type II diabetes. Four of these
studies are available to you free in full (links below).
Apple phytochemicals and their health benefits, Nutr J.
Diabetes and weight loss
Not only may apples help decrease the risk of heart
disease, cancer, and asthma, but apple consumption may also be associated
with a lower risk for diabetes. In the previously discussed Finnish study of
10,000 people, a reduced risk of Type II diabetes was associated with apple
consumption . Higher quercetin
intake, a major component of apple peels, was also associated with a
decreased risk in type II diabetes. Myrectin and berry intake were
also associated with a decreased risk in type II diabetes, but onion,
orange, grapefruit and white cabbage intake were not associated with a
Apple and pear intake has also been associated with weight
loss in middle aged overweight women in Brazil . Approximately 400 hypercholestemic, but nonsmoking, women were randomized to one of three
supplement groups: oat cookies, apples or pears, and each subject consumed
one of each supplement three times per day for twelve weeks. The
participants who consumed either of the fruits had a significant weight loss
after 12 weeks of 1.21 kg, whereas those consuming the oat cookies did not
have a significant weight loss.
Those consuming fruit also had a significantly lower blood glucose level
when compared to those consuming the oat cookies .
16. Knekt P, Kumpulainen J, Jarvinen R, Rissanen H,
Heliovaara M, Reunanen A, Hakulinen T, Aromaa A. Flavonoid intake and risk
of chronic diseases. Am J Clin Nutr 2002;76:560–568.
30. de Oliviera M, Sichieri R, Moura A. Weight
loss associated with a daily intake of three apples or three pears among
overweight women. Nutr 2003;19:253–256.
hyperglycemia with phloridzin restores the glucagon response to glucose in
insulin-deficient dogs: implications for human diabetes.
Grundy S, McGarry JD, Unger RH.
In insulin-deprived alloxan-induced diabetic dogs with severe hyperglycemia
and marked hyperglucagonemia, glucagon was not suppressed by intravenous
infusion of glucose at a progressively increasing rate up to 24 mg/kg of
body weight per min. However, when
the hyperglycemia was corrected by phloridzin, a blocker of renal tubular
glucose reabsorption, the hyperglucagonemia was readily suppressed by
as little as 2 mg of glucose per kg/min. Direct perfusion of phloridzin into
the isolated pancreas of nondiabetic dogs had no effect on the in vitro
glucagon response to increments in glucose. However, in pancreata isolated
from dogs whose glucose levels had been lowered by phloridzin pretreatment,
in vitro glucagon suppression in response to glucose increments was more
than twice that of controls. This
enhancing effect of phloridzin treatment was completely abolished by
giving an intravenous infusion of glucose for the 5 hr prior to surgery for
isolation of the pancreas. It is concluded that (i) alpha cells have a
glucose-sensing system that is independent of insulin and beta cells, and
(ii) this system is reversibly attenuated by hyperglycemia. Thus,
hyperglycemia, a metabolic consequence of islet cell dysfunction, may be a
self-exacerbating inducer of further islet cell dysfunction,
a possibility with implications for
The in vivo results indicate
that suppression of glucagon by glucose, which is absent in uncontrolled
diabetes, can be restored despite continuing insulin deficiency if
hyperglycemia is abolished by phloridzin treatment.
PMID: 3883362 [PubMed - indexed for MEDLINE]
J Clin Invest.
of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in
Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo
Insulin resistance is characteristic of the diabetic state. To define the
role of hyperglycemia in generation of the insulin resistance, we examined
the effect of phlorizin treatment on tissue sensitivity to insulin in
partially pancreatectomized rats. Five groups were studied: group I,
sham-operated controls; group II, partially pancreatectomized diabetic rats
with moderate glucose intolerance; group III, diabetic rats treated with
phlorizin to normalize glucose tolerance; group IV, phlorizin-treated
controls; and group V, phlorizin-treated diabetic rats restudied after
discontinuation of phlorizin. Insulin sensitivity was assessed with the
euglyemic hyperinsulinemic clamp technique in awake, unstressed rats.
Insulin-mediated glucose metabolism was reduced by approximately 30% (P less
than 0.001) in diabetic rats. Phlorizin treatment of diabetic rats completely normalized insulin
sensitivity but had no effect on insulin action in controls.
Discontinuation of phlorizin in
phlorizin-treated diabetic rats resulted in the reemergence of insulin
resistance. These data demonstrate that a reduction of beta-cell mass
leads to the development of insulin resistance, and
correction of hyperglycemia with
phlorizin, without change in insulin levels, normalizes insulin sensitivity.
These results provide the first in vivo evidence that hyperglycemia per se
can lead to the development of insulin resistance.
PMID: 3571496 [PubMed - indexed for MEDLINE]
of Clinical Nutrition, Vol. 76, No. 3, 560-568, September 2002
Paul Knekt, Jorma Kumpulainen, Ritva Järvinen, Harri Rissanen, Markku
Heliövaara, Antti Reunanen, Timo Hakulinen and Arpo Aromaa
Background:Flavonoids are effective
antioxidants and may protectagainst several chronic diseases.
The association between flavonoid intake and riskof several
chronic diseases was studied.
Design: The total dietary intakes of 10 054 men and women duringthe year preceding the baseline examination were determined
with a dietary history method. Flavonoid intakes were estimated,
mainly on the basis of the flavonoid concentrations in Finnish
foods. The incident cases of the diseases considered were identifiedfrom different national public health registers.
Persons with higher quercetin intakes had lower mortalityfrom
ischemic heart disease. The relative risk (RR) betweenthe
highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99:P
for trend = 0.02). The incidence of cerebrovascular diseasewas
lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003),
naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80;0.64, 0.99; P = 0.008) intakes. Men with higher
intakeshad a lower lung cancer incidence (0.42; 0.25, 0.72; P
= 0.001),and men with higher myricetin intakes had a lower
prostate cancerrisk (0.43; 0.22, 0.86; P = 0.002). Asthma
incidence was lowerat higher
quercetin (0.76; 0.56, 1.01; P
= 0.005), naringenin(0.69; 0.50, 0.94; P = 0.06), and
hesperetin (0.64; 0.46, 0.88;P = 0.03) intakes.
A trend toward a reduction in risk
of type2 diabetes was associated with higher quercetin
(0.81; 0.64,1.02; P = 0.07) and myricetin (0.79; 0.62,
1.00; P = 0.07) intakes.
The risk of some chronic diseases may be lower athigher dietary
improves hyperglycemia but not hepatic insulin resistance in a transgenic
mouse model of type 2 diabetes.
Zhao H, Yakar S, Gavrilova O, Sun H, Zhang Y, Kim H,
Setser J, Jou W, LeRoith D.
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892-1758, USA.
In a previous study
(6,7), we developed a transgenic mouse that expresses a dominant-negative
IGF-1 receptor (IGF-1R) specifically in skeletal muscle (the MKR mouse
model). The formation of hybrid receptors between the mutant and endogenous
IGF-1 and insulin hemireceptors markedly inhibited both IGF-1R and insulin
receptor activity. This led to severe insulin resistance in muscle, which
then caused secondary insulin resistance to develop in liver and adipose
tissue. MKR mice exhibit β-cell dysfunction, hyperinsulinemia, dyslipidemia,
and hyperglycemia. Thus, the MKR
mouse is an excellent model for studying the molecular mechanisms underlying
the development of type 2 diabetes (6).
Phloridzin (PHZ) is an
antidiabetic agent that is found
primarily in apple peels (10). PHZ inhibits intestinal glucose uptake
via the sodium D-glucose cotransporter and similarly inhibits renal glucose
reabsorption (11,12). Correction of hyperglycemia with PHZ has been
shown to normalize the effects of
insulin on glucose metabolism in the liver and other peripheral tissues
such as muscle and adipose tissue in diabetic rat models (13).
β-Cell abnormalities were also
completely corrected when diabetic rats were treated with PHZ to normalize
plasma glucose levels (14). Muscle-specific GLUT4 knockout mice
showed severe insulin resistance and glucose intolerance from 8 weeks of age
(15). When these mice were treated
with PHZ, insulin-stimulated glucose uptake in adipose tissue and
insulin-induced suppression of hepatic glucose production were normalized,
whereas insulin-stimulated whole-body and skeletal muscle glucose uptake
remained decreased (16).
PHZ treatment improves hyperglycemia
without affecting dyslipidemia or hyperinsulinemia in MKR mice. At
the age of 6-8 weeks, male MKR mice had higher blood and urine glucose
levels, higher serum triglycerides, and hyperinsulinemia compared with WT
mice (Fig. 1). Two weeks of PHZ
treatment significantly decreased blood glucose levels in MKR mice
(from 345 27.7 to 212 17.0 mg/ dl). However, PHZ had no effect on blood
glucose levels in the WT mice (Fig. 1A). PHZ treatment significantly
increased urine glucose levels in both MKR and WT mice, as compared with
vehicle-treated littermates, which
confirmed a functional effect of PHZ (Fig. LB). However, serum
triglycerides and insulin levels were not changed in response to PHZ
treatment. Free fatty acid level was significantly reduced in PHZ-treated WT
mice; however, it was not changed in PHZ- treated MKR mice (Fig. 1C-E).
PHZ treatment decreases fat mass in MKR mice. Compared with WT controls, vehicle-treated MKR mice had
slightly lower average body weights (Fig. 2A). Body composition analysis
showed that MKR mice had 30% higher levels of fat mass and 20% lower levels
of lean mass than WT mice (Fig. 2B-C).
Whole-body fat mass in MKR mice was
significantly reduced in response to PHZ treatment (1.40 0.18 vs.
2.29 0.16 g in vehicle-treated MKR mice). In contrast, PHZ treatment had no
effect on fat mass in WT mice. PHZ treatment had no effect on lean mass in
either MKR or WT mice
In conclusion, MKR
mice, which exhibit severe insulin resistance and diabetes,
exhibit improved circulating glucose
levels in response to treatment with PHZ. However, this effect on
circulating blood glucose levels was not associated with any improvements in
whole-body insulin sensitivity or glucose homeostasis. These data suggest
that lipotoxicity, but not glucotoxicity, plays a major role in the
development and progression of type 2 diabetes in this animal model
PMID: 15504971 [PubMed
- in process]
6. Fernandez AM, Kim JK,
Yakar S, Dupont J, Hernandez-Sanchez C, Castle AL, Filmore J, Shulman GI, Le
Roith D: Functional inactivation of the IGF-I and insulin receptors in
skeletal muscle causes type 2 diabetes. Genes Dev 15:1926-1934, 2001
7. Fernandez AM, Dupont J, Farrar RP, Lee S, Stannard B, LeRoith D:
Muscle-specific inactivation of the IGF-I receptor induces compensatory
hyperplasia in skeletal muscle. J Clin Invest 109:347- 355, 2002
8. Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I: Central role
of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in
mice. Hepatology 38:123-132, 2003
9. Kim H, Haluzik M, Asghar Z, Yau D, Joseph JW, Fernandez AM, Reitman ML,
Yakar S, Stannard B, Heron-Milhavet L, Wheeler MB, LeRoith D: Peroxisome
proliferator-activated receptor-α agonist treatment in a transgenic model of
type 2 diabetes reverses the lipotoxic state and improves glucose
homeostasis. Diabetes 52:1770- 1778, 2003
10. Crespy V, Aprikian O, Morand C, Besson C, Manach C, Demigne C, Remesy C:
Bioavailability of phloretin and phloridzin in rats. J Nutr 131:3227-3230,
11. Boccia MM, Kopf SR, Baratti CM: Phlorizin, a competitive inhibitor of
glucose transport, facilitates memory storage in mice. Neurobiol Learn Mem
12. Burcelin R, Mrejen C, Decaux JF, De Mouzon SH, Girard J, Charron MJ: In
vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration
by glucose metabolism. J Biol Chem 273:8088-8093, 1998
13. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA: Correction
of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in
diabetic rats. J Clin Invest 79:1510- 1515, 1987
14. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA: Effect of chronic
hyperglycemia on in vivo insulin secretion in partially pancreatectomized
rats. J Clin Invest 80:1037-1044, 1987
15. Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB,
Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, Kahn CR, Kahn BB:
Targeted disruption of the glucose transporter 4 selectively in muscle
causes insulin resistance and glucose intolerance. Nat Med 6:924-928, 2000
16. Kim JK, Zisman A, Fillmore JJ, Peroni OD, Kotani K, Perret P, Zong H,
Dong J, Kahn CR, Kahn BB, Shulman GI: Glucose toxicity and the development
of diabetes in mice with muscle-specific inactivation of GLUT4. J Clin
Invest 108:153-160, 2001
J Tongji Med Univ.
study on the treatment of diabetes by phloridzin in rats.
Zhang S, Zhu M, Shen D.
Xiehe Hospital, Tongji Medical University, Wuhan.
Male rats at six weeks of age were divided into 5 groups at random: in group
I, the rats with diabetes received 70% pancreatectomy; group II had
sham-operation serving as controls; diabetic rats in group III were treated
with phloridzin; In group IV rats received sham-operation and phloridzin
treatment and group V were phloridzin-treated diabetic rats to be studied
after discontinuance of phloridzin. 70 days after surgery, the weights and
insulin contents of operated remnant pancreas were markedly higher than the
expected value of 30%, reaching 44% (48.2% +/- 15.2%), demonstrating that
the remnant pancreas still had capacities of compensatory regeneration and
diabetic rats completely returned to normal in terms of oral glucose
tolerance and insulin sensitivity. Discontinuation of phloridzin
treatment in diabetic rats resulted in the recurrence of insulin resistance.
These results suggested that normalization of hyperglycemia could ameliorate
insulin resistance under diabetic conditions.
PMID: 10806836 [PubMed - indexed for MEDLINE]
Asia Pac J Clin Nutr.
fatty acid (NEFA) and insulinemic responses to watermelon and apple in type
2 diabetic subjects.
Fatema K, Habib B, Afza N, Ali L.
Biomedical Research Group, BIRDEM.
Background - Glycemic Index (GI), Insulin and Non-esterified Fatty Acid (NEFA)
responses are useful measures for the biological effects of a carbohydrate
diet in relation to diabetes and its complications. Objective - To determine
those indicators in Watermelon and Apple to help in establishing a balanced
and better food exchange table for the
diabetic patients in Bangladesh. White
bread (WB) was used as the reference food. Design - 13 subjects (8 male and
5 female) under a crossover design, consumed equi-carbohydrate amount of the
fruits and bread, with a run-in period of 7 days between the consecutive
items. Serum C-peptide was used as the marker of insulin and it was measured
by ELISA, HbA(1)c and NEFA were HPLC and Colorimetric methods respectively.
Outcomes - Watermelon and Apple had almost similar glycemic response which
were lower than WB and its reflected in their GI values (Apple 94 +/-19,
Watermelon 92 +/- 15). Insulin responses were similar in Apple (0.62
+/-1.13) and in Watermelon (0.45 +/- 0.72) and they had a significantly
lower Absolute Change (AC) of C-peptide compared to bread (P=0.001 in WB vs
Apple and P<0.001 in WB vs Watermelon). There was a lower NEFA response of
Watermelon compared with Apple and WB but the difference was not
significant. Conclusions - a) Equi-carbohydrate of Apple, Watermelon and WB
produce almost similar glycemic response.
The dynamics of blood glucose
changes (avoidance of sharp peak) with Apple, however, makes it a better
choice compared to the other two. b) Watermelon maintains a glycemic
response similar to Apple and WB at the expense of lower insulin response
and may have beneficial effect on dyslipidemia.
PMID: 15023673 [PubMed - in process]
the Science of Food and Agriculture,
Volume 82, Issue 15 , Pages 1800 - 1805,
23 Oct 2002
role for apple juice phenolic compounds in the acute modification of glucose
tolerance and gastrointestinal hormone secretion in humans
Johnston, Michael N Clifford, Linda M Morgan * Centre for Nutrition and Food Safety, School
of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2
to Linda M Morgan, Centre for Nutrition and Food Safety, School of
Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2
of this study was to investigate whether naturally occurring
phenolic compounds in apple juice
had any physiological effects on plasma glucose concentrations and
circulating gastrointestinal hormone profiles in volunteers.
The results show that the
consumption of a 25 g glucose load in commercial apple juice compared with
that consumed in water has statistically significant effects on plasma
concentrations of glucose, insulin, GIP and GLP-1 in volunteers (N = 9)
which appear to be consistent with
delayed intestinal absorption of glucose. The exact mechanisms
require further investigation but, tentatively, it is suggested that
phloridzin and other polyphenols
may be responsible.