A Review of the Antidiabetic Activities of Ginger

Diabetes mellitus, a chronic metabolic disorder with major health care burden worldwide, is increasing, with 173 million adults being diabetic and over 8 million deaths recorded annually. Undesirable pathological conditions and high rates of secondary failure limit the use of current antidiabetic agents, thus, the need for more effective antidiabetic agents. Medicinal plants such as spices, rich in bioactive components that promote prevention and treatment of chronic conditions such as heart disease, cancer and Type-2 diabetes, are inexpensive with no side effects. The Zingiberaceae family, of which ginger is a member, consists of many species frequently cited for their antidiabetic and hypoglycemic properties. All important scientific literatures from 2000 to 2018 on the antidiabetic potentials of Zingiber officinale were evaluated. According to these studies, ginger exerts its antidiabetic effects through restorative effects on pancreatic β -cells, increasing insulin sensitivity, action and peripheral utilization of glucose. Other mechanisms include increased synthesis of hepatic glycogen through the enhancement of glycogen regulatory enzyme expression in the liver, inhibition of carbohydrate metabolizing enzymes, stimulation of pancreatic insulin release and inhibition of hepatic glucose production. Further studies, especially in humans are needed, more so, since ginger is one of the spices generally regarded as safe.


Introduction
Diabetes mellitus (DM) is the most common endocrine disorder that affects more than 100 million people worldwide. It is a heterogeneous group of diseases, all of which ultimately lead to an elevation of glucose in the blood (hyperglycemia) and loss of glucose in the urine as hyperglycemia increases. It is characterized by increased urine production (polyurea) excessive thirst (polydipsia) and excessive eating (polyphagia).
Diabetes mellitus is a chronic metabolic disorder of the endocrine system that is characterized by defects in impaired metabolism of glucose, lipid and protein as well as insulin secretion or insufficiency. Diabetes continues to be a major health care problem worldwide and its prevalence is expected to rise from the current 382-471 million individuals by 2035 [1,2]. There are three main types of diabetes-Type 1 diabetes (T1D), which is an autoimmune disorder leading to the destruction of pancreatic beta-cells; Type 2 diabetes (T2D), which is much more common and primarily caused by impaired glucose regulation due to a combination of dysfunctional pancreatic beta cells and insulin resistance and gestational diabetes mellitus (GDM). DOI: http://dx.doi.org /10.5772/intechopen.88899 Administration (FDA) as a food additive that is "generally recognized as safe" [14] and has a long history of use as a culinary spice and in herbal medicine to treat many ailments.

Antidiabetic properties of ginger
Lamuchi-Deli et al. [29] evaluated the effects of the hydroalcoholic extract of Zingiber officinale on arginase I activity and expression in the retina of streptozotocin-induced diabetic rats. The study showed that blood glucose concentration was significantly decreased, arginase I activity and expression was significantly (P < 0.05) down regulated and 400 mg/kg of the extract reduced significant elevation in body weight in diabetic rats compared to untreated diabetic controls (P < 0.01). Serum insulin was also significantly increased in diabetic rats treated with 400 mg/kg of the extract compared to diabetic controls (P < 0.05). The study suggested that ginger could be a promising therapeutic option for treating diabetesinduced vascular disorders.
A recent study by de Las Heras et al. [30] which evaluated the hypolipidemicand insulin sensitizing effects of hydroethanolic extract of ginger in the liver of high-fat diet (HFD) fed rats, revealed that ginger extract improved lipid profile and attenuated the increase of plasma levels of glucose, insulin, and leptin in HFD rats. Wei et al. [31], also reported that 6-Paradol and 6-Shogaol, the pungent compounds of ginger, promoted glucose utilization in adipocytes and myotubes, and 6-paradol reduced blood glucose in HFD-fed mice. Al-Qudah et al. [32] reported that aqueous extract of ginger was effective in lowering serum glucose, restoration of hematological indices to normal and repair damaged pancreas in alloxan-induced diabetic rats.
In another study, Oludoyin and Adegoke [33] investigated the effect of ginger extracts on blood glucose in normal and streptozotocin-induced diabetic rats. The authors reported that the fasting blood glucose in diabetic rats was reduced to normal by both raw and cooked ginger extracts in a manner comparable to glibenclamide. Evaluation of the nutritional and antidiabetic activity of ginger powder, its aqueous and methanolic extract, as well as the essential oil in streptozotocininduced diabetic rats [34] revealed reduction in levels of alanine and aspartate aminotransferase (ALT and AST), alkaline phosphatase (ALP), liver total lipid and cholesterol of diabetic rats; and increased levels of liver glycogen and triglyceride compared to positive control group. In the study, ginger oil showed the best antidiabetic activity, followed by ginger extracts. Again, another study reported that ginger extract administered at 200 mg/kg/day/kg body weight for 10 weeks to male Sprague-Dawley diabetic rats, exhibited protective activity against insulin resistance [34].
Al-Noory et al. [35] showed that fresh ginger extracts led to decrease in the levels of total cholesterol (TC) and low density lipoprotein (LDL) in the serum of alloxan-induced diabetic rats, compared with the control groups; and previous extracts caused reduction in LDL to levels comparable to normal group and equal to the effect of atorvastatin given at a dosage of 10 mg/day. Similarly, oral administration of aqueous ginger extract to streptozotocin (STZ)-induced diabetic rats for a period of 30 days was reported to give a dose-dependent antihyperglycemic effect, 68% decrease in plasma glucose level at a daily dose of 500 mg/kg body weight, indicating that ginger is a potential phytomedicine for the treatment of diabetes [36]. Iranloye et al. [37] also showed that ginger effectively reduced fasting blood glucose, malondialdehyde levels and enhanced insulin sensitivity in alloxaninduced and insulin-resistant diabetic rats compared to control rats.
Treatment of streptozotocin-induced Type I diabetic rats with Z. officinale juice (4 mL kg −1 , p.o. daily for 6 weeks) was reported to produce a significant increase in insulin levels, decrease in fasting glucose levels, as well as significant decrease in the area under the curve of glucose in an oral glucose tolerance test [38]. According to Nammi et al. [23], treatment with an ethanolic extract of ginger at doses of 100, 200, and 400 mg/kg for 6 weeks, significantly reduced the marked increase in body weight, serum glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, free fatty acid and phospholipids induced by high-fat diet.
The study conducted by Al-Amin et al. [39] on the antidiabetic and hypolipidemic properties of ginger (Zingiber officinale) in streptozotocin-induced diabetic rats revealed that raw ginger at a dose of 500 mg/kg, was significantly effective in lowering serum glucose, cholesterol and triacylglycerol as well as reduction in urine protein (reversal of diabetic proteinuria) levels, of diabetic rats. Ethanolic extracts of Zingiber officinale (200 mg/kg) given orally for 20 days was reported to produce significant antihyperglycemic effect (P < 0.01) in diabetic rats, while also lowering serum total cholesterol and triglycerides, coupled with increased HDL-cholesterol levels when compared with pathogenic diabetic rats [40].
Hypoglycemic effect of ginger (4 and 8 g/kg), administered intraperitoneally to rats after 30 min of diabetes induction, with the effect being more pronounced after 2 h has been reported. In another study, Otunola and Afolayan [41], showed that aqueous extract of a spice mixture containing ginger at 500 mg/kg body weight extract significantly (p < 0.05) lowered the elevated fasting blood glucose, lipid and hematological indices of alloxan-induced diabetic rats at equipotent level with glibenclamide. DOI: http://dx.doi.org /10.5772/intechopen.88899 Several in vitro hypoglycemic potentials of ginger and its bioactive constituents especially 6-shogaol have been reported ( Table 1).
The capacity of ginger for hypoglycemic, antidiabetic, insulogenic, better glucose tolerance, increased serum insulin levels, reduction in elevated lipid levels, and prevention of weight loss associated with diabetes in human diabetic patients have also been reported ( Table 2).

Mechanism of action
Various mechanisms have been proposed for the antidiabetic and hypoglycemic activities of medicinal plants. These include peripheral utilization of glucose, increased synthesis of hepatic glycogen by enhancement of glycogen regulatory enzyme expression in the liver, inhibition of carbohydrate metabolizing enzymes, stimulation of pancreatic insulin release, insulomimetic actions and inhibition of hepatic glucose production [55,56].
According to Dearlove et al. [57], spices such as cinnamon, cloves, oregano, and allspice possess bioactive compounds that have (1) antiglycation properties which inhibit the formation of AGEs; (2) (3) anti-inflammatory potentials. Some studies associate the antidiabetic action of ginger to its bioactive principles such as gingerol and shogaol which have the capacity to enhance glucose uptake in rat's skeletal muscle cells, and promote increased expression and translocation of GLUT-4 glucose transporter to the plasma membrane of the cells thus clearing excess glucose from the serum [34]. Another mechanism proposed was the inhibition of key enzymes of carbohydrate metabolism-α-glucosidase and α-amylase by phenolic compounds (gingerols and shogaols) present in ginger [23,45]; while other authors showed that ginger increases muscle and liver glycogen stores by enhancing peripheral utilization of glucose, thus limiting gluconeogenesis in the liver and kidney in a manner similar to insulin [37].
Son et al. [58], posits that-gingerol exerts its antidiabetic effects through multiple mechanisms that include-(1) increased glucose uptake in the absence  of insulin, (2) induction of 5′ adenosine monophosphate-activated protein kinase phosphorylation, (3) promotion of glucose transporter 4 (GLUT4) translocation to plasma membrane, (4) suppression of advanced glycation end product-induced rise of ROS levels in pancreatic β-cells, (5) reduction of fasting blood glucose levels and improved glucose intolerance, (6) regulation of hepatic gene expression of enzymes involved in glucose metabolism toward decreased gluconeogenesis and glycogenolysis, while increasing glycogenesis, thereby reducing blood glucose concentrations.

Conclusion
This study presented an update on the antidiabetic potentials of ginger from the Zingiberaceae family. Although several in vivo and in vitro reports were available, there were relatively few clinical (human) trials. The doses and outcomes also varied; as well as the mechanism of action through which antidiabetic effects were mediated. Although these reports are indicative of the anti-diabetic or hypoglycemic potentials of ginger, the doses and outcomes also varied; most importantly, the mechanisms of action through which anti-diabetic effects are mediated were highlighted. Ginger, according to these studies, exerts its anti-diabetic effects through restorative effects on pancreatic β-cells, increasing insulin sensitivity, insulin-like action and peripheral utilization of glucose. Other mechanisms include increased synthesis of hepatic glycogen through the enhancement of glycogen regulatory enzyme expression in the liver, inhibition of carbohydrate metabolizing enzymes, stimulation of pancreatic insulin release, and inhibition of hepatic glucose production. However, further studies, especially in humans are therefore needed and the oral safety of the various extracts under prolonged usage must be confirmed, more so, since ginger is one of the spices generally regarded as safe.