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• Apple polyphenols and apple juice show benefits in lowering and stabilizing blood glucose levels, hyperglycemia, and insulin sensitivity in both animal and human studies.

• In one study, an isolated apple polyphenol extract "completely normalized insulin sensitivity" in diabetic rats.

• In another study, this same apple extract "completely returned to normal in terms of oral glucose tolerance and insulin sensitivity."

• These studies discuss apple polyphenols and their effectiveness in human trials on Type II diabetes. Four of these studies are available to you free in full (links below).

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 [16]. 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 lowered risk.

Apple and pear intake has also been associated with weight loss in middle aged overweight women in Brazil [30]. 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 [30].

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.

Download the full study here

Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats, J Clin Invest. 1987

Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes.

Starke A, Grundy S, McGarry JD, Unger RH.

Abstract:

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 human diabetes.

Excerpts:

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]

Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.

Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA.

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]

© 2002 American Society for Clinical Nutrition

Original Research Communication

Flavonoid intake and risk of chronic diseases^1,2

Paul Knekt, Jorma Kumpulainen, Ritva Järvinen, Harri Rissanen, Markku Heliövaara, Antti Reunanen, Timo Hakulinen and Arpo Aromaa

Background: Flavonoids are effective antioxidants and may protect against several chronic diseases.

Objective: The association between flavonoid intake and risk of several chronic diseases was studied.

Design: The total dietary intakes of 10 054 men and women during the 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 identified from different national public health registers.

Results: Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was 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 quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at 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 type 2 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.

Conclusion: The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.

Key Words: Chronic disease • diet • flavonoids • flavonols • flavanones • flavones • prospective study • free radicals

[Reprint (PDF) Version of Full Study]

Phloridzin 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.

EXCERPTS:

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).

RESULTS

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, 2001

11. Boccia MM, Kopf SR, Baratti CM: Phlorizin, a competitive inhibitor of glucose transport, facilitates memory storage in mice. Neurobiol Learn Mem 71:104-112, 1999

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

Experimental 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 proliferation capacities. Phloridzin-treated 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]

Glycemic, non-esterified 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]

Kelly L 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 7XH, UK

^*Correspondence to Linda M Morgan, Centre for Nutrition and Food Safety, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK

 Abstract

The purpose 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.

© 2002 Society of Chemical Industry

Received: 18 March 2002; Revised: 3 July 2002; Accepted: 6 August 2002