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Frontiers of Medicine

Front Med    2013, Vol. 7 Issue (1) : 31-52     DOI: 10.1007/s11684-013-0251-9
REVIEW |
Zinc homeostasis in the metabolic syndrome and diabetes
Xiao Miao1,3, Weixia Sun2,3, Yaowen Fu2, Lining Miao1, Lu Cai3,4,5()
1. The Second Hospital of Jilin University, Changchun 130021, China; 2. The Organ Transplantation Center, the First Hospital of Jilin University, Changchun 130021, China; 3. KCHRI at the Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; 4. Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Wenzhou 325035, China; 5. Departments of Radiation Oncology and Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
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Abstract

Zinc (Zn) is an essential mineral that is required for various cellular functions. Zn dyshomeostasis always is related to certain disorders such as metabolic syndrome, diabetes and diabetic complications. The associations of Zn with metabolic syndrome, diabetes and diabetic complications, thus, stem from the multiple roles of Zn: (1) a constructive component of many important enzymes or proteins, (2) a requirement for insulin storage and secretion, (3) a direct or indirect antioxidant action, and (4) an insulin-like action. However, whether there is a clear cause-and-effect relationship of Zn with metabolic syndrome, diabetes, or diabetic complications remains unclear. In fact, it is known that Zn deficiency is a common phenomenon in diabetic patients. Chronic low intake of Zn was associated with the increased risk of diabetes and diabetes also impairs Zn metabolism. Theoretically Zn supplementation should prevent the metabolic syndrome, diabetes, and diabetic complications; however, limited available data are not always supportive of the above notion. Therefore, this review has tried to summarize these pieces of available information, possible mechanisms by which Zn prevents the metabolic syndrome, diabetes, and diabetic complications. In the final part, what are the current issues for Zn supplementation were also discussed.

Keywords zinc      zinc transporters      metallothionein      diabetes      diabetic complications      insulin resistance      antioxidant     
Corresponding Authors: Cai Lu,Email:L0cai001@louisville.edu   
Issue Date: 05 March 2013
 Cite this article:   
Xiao Miao,Weixia Sun,Yaowen Fu, et al. Zinc homeostasis in the metabolic syndrome and diabetes[J]. Front Med, 2013, 7(1): 31-52.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-013-0251-9
http://journal.hep.com.cn/fmd/EN/Y2013/V7/I1/31
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Fig.1  Subcellular localization of Zn transporters and MTs. Localization and potential functions of Zn transporters from the Slc39/ZIP (blue) and Slc30/ZnT (red) families, MT, and metal response element (MRE)-binding transcription factor 1 (MTF1) within the cell. Arrows show the predicted direction of Zn mobilization. ER, endoplasmic reticulum. The figure was made based on the previous report [].
Fig.1  Subcellular localization of Zn transporters and MTs. Localization and potential functions of Zn transporters from the Slc39/ZIP (blue) and Slc30/ZnT (red) families, MT, and metal response element (MRE)-binding transcription factor 1 (MTF1) within the cell. Arrows show the predicted direction of Zn mobilization. ER, endoplasmic reticulum. The figure was made based on the previous report [].
Injection, i.p. (10 mg/kg)MT inductionRats, STZ single dose (75 mg/kg)++Yang & Cherian[173]
Drinking (20 mmol/L), 8 weeksMT(ND)ob/ob mice++++Chen et al. [174]
Dietary (1000 ppm), 4 weeksMT(ND)Pro-diabetic BB Wister rats++++Tobia et al. [175]
Drinking (25 mmol/L), 1 weekMT inductionC57BL/6 & B6SJL/F1 mice++++Ohly et al. [80]
5 × 40 mg STZ/kg
Dietary (300 ppm), 6 weeksMT(ND)db/db mice++++Simon & Taylor [176]
Dietary (1000 ppm), 2 weeksMT inductionCD-1 mice, ALX (50 mg/kg)++++Ho et al. [177]
STZ (5× 40 mg/kg)++++Ho et al. [177]
Drinking (25 mmol/L), 1 (12) weeksMT(ND)C57BL/6, ALX (50 mg/kg)+++im Walde et al. [178]
Drinking (25 mmol/L), 1 weekInhibiting NF-κBC57BL/6 mice++++Schott-Ohly et al. [179]
&/or AP1NOD
Dietary (15 mg/kg), 2 weeksKK-Ay mice+++Yoshikawa et al. [180]
Injection, i.p. (1.5-3 mg/kg), 4 weeksKK-Ay mice+++Yoshikawa et al. [180]
Genetic enhancing MTZn-MTMT-TG mice, STZ (1 × 200 mg/kg)++++Chen et al. [181]
Tab.1  Evidence for the preventive effect of Zn supplementation on diabetes
Fig.2  Effects of Zn supplementation on insulin resistance and plasma glucose level in obese children. * <0.05 vs. before receiving either Zn or placebo. The figure was made based on published study [].
Fig.2  Effects of Zn supplementation on insulin resistance and plasma glucose level in obese children. * <0.05 vs. before receiving either Zn or placebo. The figure was made based on published study [].
Type of studiesZn pretreatmentsTarget tissuesReferences
Human studies
Elderly diabetic patientsSerum Zn level correctionKajanachumol et al. [139]
Enhancing CD4 lymphocytes
IDDM patients30 mg/d Zn gluconateSerum Zn level correctionFaure et al. [182]
× 3 monthsTBRAS decrease
Se-GPx increase in patients with retinopathy
DM patients/neuropathy660 mg/d ZnSO4Serum Zn correctionGupta et al. [183]
× 6 weeksImprovement of neuropathy severity
IDDM patients30 mg Zn × 3 monthsPrevented diabetic nephropathyParham et al. [184]
IDDM patients30 mg Zn × 3 monthsPrevented diabetic nephropathyHeidarian et al. [185]
Animal studies
STZ diabetic rats25 mg/kg ZnSO4No prevention of bone lossYamaguchi &amp; Uchiyama [186]
25 mg/kg Zn acexamatePrevention of bone loss
(oral, × 2 weeks)
STZ diabetic rats25, 50 or 100 mg/kg, oralUchiyama &amp; Yamaguchi [187]
ZnSO4No prevention of bone loss
Zn acexamatePrevention of bone loss
ALX diabetic rats5 mg/kg ZnCl2, oncePrevention of retinal &amp; hepatic GHSMoustafa [188]
Decreased retinal &amp; hepatic TBARS
STZ diabetic mice5 mg/kg ZnSO4, × 13 daysPrevented diabetic embryonic cardiotoxicityKumar et al. [189]
STZ diabetic rats100 mg/kg (drinking water)Prevented diabetic damage in the kidneyKaratug et al. [190]
Tab.2  Evidence for the preventive effect of Zn supplementation on diabetic complications
Fig.3  Effect of Zn supplementation on serum glucose and lipid levels in type 2 diabetic patients. The figures were made based on the recent meta-analysis of type 2 diabetic patients with and without Zn supplementation. The decreased effects (<0.05 or<0.01) of Zn supplementation (black bars) on the measurements were pooled from several studies and compared to placebo (level of zero). FBG: fasting blood glucose; HbA1c: glycated hemoglobin; TC: total cholesterol; LDLc: low density lipid cholesterol. The figures were made based on the meta-analysis [].
Fig.3  Effect of Zn supplementation on serum glucose and lipid levels in type 2 diabetic patients. The figures were made based on the recent meta-analysis of type 2 diabetic patients with and without Zn supplementation. The decreased effects (<0.05 or<0.01) of Zn supplementation (black bars) on the measurements were pooled from several studies and compared to placebo (level of zero). FBG: fasting blood glucose; HbA1c: glycated hemoglobin; TC: total cholesterol; LDLc: low density lipid cholesterol. The figures were made based on the meta-analysis [].
Fig.4  Effect of Zn on Nrf2/ARE pathway. In normal conditions, Keap1 sequesters Nrf2 in the cytosol and targets it for degradation. Small amount of ROS alter the interaction between Nrf2 and Keap1, leading to Nrf2 accumulation and degradation in the cytoplasm. Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE) to turn on the expression of protective genes. Prolonged oxidative stress activates GSK-3β to phosphorylate Fyn. The phosphorylated Fyn then translocates to the nucleus where Fyn phosphorylates Nrf2, leading to the exportation of Nrf2 to the cytoplasm. In the cytoplasm Nrf2 will be bound by Keap 1, leading to Nrf2 degradation. Zn is able to stimulate Akt phosphorylation to inhibit GSK-3β function to reduce Fyn phosphorylation, resulting in Nrf2 accumulation in nuclear to turn on its down-stream antioxidants.
Fig.4  Effect of Zn on Nrf2/ARE pathway. In normal conditions, Keap1 sequesters Nrf2 in the cytosol and targets it for degradation. Small amount of ROS alter the interaction between Nrf2 and Keap1, leading to Nrf2 accumulation and degradation in the cytoplasm. Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE) to turn on the expression of protective genes. Prolonged oxidative stress activates GSK-3β to phosphorylate Fyn. The phosphorylated Fyn then translocates to the nucleus where Fyn phosphorylates Nrf2, leading to the exportation of Nrf2 to the cytoplasm. In the cytoplasm Nrf2 will be bound by Keap 1, leading to Nrf2 degradation. Zn is able to stimulate Akt phosphorylation to inhibit GSK-3β function to reduce Fyn phosphorylation, resulting in Nrf2 accumulation in nuclear to turn on its down-stream antioxidants.
AbbreviatesFull namesOutcomeReferences
Zn(bet)2Zn(II)/βine+++Kojima et al. [191]
Zn(lac)2Zn(II)/L-lactic acid+++
Zn(qui)2Zn(II)/quinic acid++++
Zn/cZn(II)/cyclo(his-pro)++++Hwang et al. [192]
Song et al. [193]
Zn(car)2Cl2Zn(II)/carnitine++++Yoshikawa et al. [194]
ZPZn(II)/bi(picolinato)Yoshikawa et al. [158]
ZMZn(II)/bis(maltolato)
ZTZn(II)/bis(threoninato)
Zn(ma)2Zn(II)/bis(maltolato)++Adachi et al. [195]
Zn(alx)2Zn(II)/bis(allixinato)++++
Zn(tpps)See note *++++Saha et al. [196]
Tab.3  Zn complexes which have been explored for reducing hyperglycemia and acting insulin function
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