Ginger in Type 2 Diabetes
Ginger

ZINGIBER OFFICINALE (GINGER)

Zingiber officinale is perennial plant, commonly known as ginger, which belogs to to the family of Zingiberaceae. The rhizomes of Zingiber officinale are an important kitchen spice and also possess a myriad of health benefits. (A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe), 2013, Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients, 2013)

For centuries the rhizome of the plant has been used for culinary aims and curing a wide range of ailments such as arthritis, rheumatism, muscular aches, constipation, indigestion, nausea, vomiting, hypertension, dementia and fever, osteoarthritis, musculoskeletal disorder, motion sickness, migraine, cancer, hyperlipidemia and hyperglycemia. (Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients, 2013)

Recent evidence revealed the potential of ginger for treatment of diabetes mellitus because of the antihyperglycaemic and antiinflammatory effects of ginger.
Ginger has shown prominent protective effects on diabetic liver and kidney complications. (Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review, 2012)

DIABETES

The prevalence of diabetes mellitus has reached epidemic proportions and has affected 6.4% of adults worldwide in 2010. Diabetes mellitus is characterised by defects in insulin release or/and insulin sensitivity resulting in a chronic hyperglycemia and is classified into two major categories, type 1 and type 2. Type 2 diabetes accounts for >90% of diabetes and is associated with metabolic disorder of lipid and carbohydrate. ( Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review, 2012)
Chronic hyperglycemia increases circulating levels of inflammatory biomarkers such as IL-6, tumor necrosis factor-α and C-reactive protein. (Anti-inflammatory effects of zingiber officinale in type 2 diabetic patients, 2013) The increased levels of circulating inflammatory cytokines may increase insulin resistance in the liver, skeletal muscles and vascular endothelium. (The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

Obesity, inflammation and diabetes

(Inflammation, stress, and diabetes, 2006)

Obesity is a risk factor for diabetes.
TNF-α, a cytokine involved in systemic inflammation, is overproduced in the adipose as well as muscle tissues of obese humans.
Overproduction of TNF-α in adipose tissue, as well as hyperlipidemia (typical in obese people), contributes significantly to insulin resistance.

Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells. The stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate (IRS) family, thus initiating downstream signaling events.

Exposure of cells to TNF-α or elevated levels of free fatty acids stimulates inhibitory phosphorylation of serine residues of IRS-1.
Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling:

• JNK phosphorylates IRS-1 on Ser307.

• PKC-θ is activated by the rise of intracellular fatty acid metabolites, such as diacylglycerol (DAG) and fatty acyl CoAs and it increases Ser307 phosphorylation of IRS-1 and activates another serine/threonine kinase, IKK or JNK.

• IKK can directly phosphorylate IRS-1 on serine residues or it can phosphorylate inhibitor of NF-κB, thus activating NF-κB, a transcription factor that, among other targets, stimulates production of multiple inflammatory mediators, including TNF-α and IL-6.

The phosphorylation of serine residues of IRS-1 reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signaling and insulin action.

Inflammatory signaling pathways can also become activated by metabolic stresses originating from inside the cell as well as by extracellular signaling molecules.
It has been demonstrated that obesity overloads the functional capacity of the ER and that this ER stress leads to the activation of inflammatory signaling pathways and thus contributes to insulin resistance.
Additionally, ROS production is elevated in obesity, which causes enhanced activation of inflammatory pathways.

EFFECTS OF GINGER IN TYPE 2 DIABETIC PATIENTS

Side effects of the presently available hyperglycaemia agents have impeded their usefulness as antidiabetic agents. This has led to continuous effort to explore effective agents for control of diabetes mellitus, such as ginger. ( Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review, 2012)

Ginger supplementation significantly:

• reduces the level of fasting plasma glucose (FPG): p=0.02
• lowers the levels of insulin: p=0.001, p=0.01
• increases the QUICKI (quantitative insulin-sensitivity check index): p=0.005
• reduces the level of HbA1C: p=0.001
• lowers the level of TG: p=0.03 (2), p=0.001
• reduces the level of total cholesterol: p=0.02
• lowers the level of LDL-C: p=0.04
• increases HDL/ total cholesterol ratio: p=0.02
• reduces the level of CRP: p=0.02, p=0.016
• reduces the level of PGE2: p=0.009
• reduces the level of TNFα: p=0.005
  (Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients, 2013, The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014, Anti-inflammatory effects of zingiber officinale in type 2 diabetic patients, 2013)

MOLECULAR MECHANISM

• It seems that ginger decreases blood glucose directly by inhibiting the intestinal glucosidase and amylase enzymes activity (causing in this way a reduction in the absorption of glucose). ( The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

• It is well established that insulin resistance in peripheral tissues is tightly associated with elevated circulating lipids and tissue lipid accumulation (typical of obese and diabetic subjects) because excessive free fatty acid and fatty acid oxidation inhibited glucose transport into peripheral tissues, the first rate in glucose metabolism. A number of studies have demonstrated that ginger possessed prominent lipid lowering effects, and subsequently increased insulin sensitivity. ( Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review, 2012)
  The hypotriglyceridemic effect of ginger may be due to increasing lipoprotein lipase enzyme (an enzyme that plays a key role in breaking down triglycerides present in chylomicrons and very low-density lipoprotein particles, releasing their fatty acids for entry into tissue cells) activity and therefore hydrolysis of circulatory TG and decreasing serum TG. ( The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

• Treatment with antioxidants improves glucose transport and tolerance in type 2 diabetic patients with insulin resistance. Gingerols, shogaols, paradols and zingerones are antioxidants. It is possible that they act by increasing the GLUT4 protein, insulin receptors and improving β-cells function. (Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients, 2013
  , The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

• (S)-⁶-gingerol enhance glucose uptake with associated activation of AMPKα, a protein that stimulate hepatic fatty acid oxidation and ketogenesis, inhibit cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibit adipocyte lipolysis and lipogenesis, stimulate skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulate insulin secretion by pancreatic beta-cells. Ginger extract, in fact, increased AMPK protein expression and AMPKαThr172 phosphorylation. (Preventative Effect of Zingiber officinale on Insulin Resistance in a High-Fat High-Carbohydrate Diet-Fed Rat Model and its Mechanism of Action, 2014)

• Ginger has another effect on insuline sensitivity, due to the activation of PPARγ (peroxisome proliferator-activated receptor gamma) for the effect of the agonistic activity of 6-shagaols, or due to the up regulation of adiponectin for the effect of 6-gingerol and 6-shagaol. Plasma adiponectin levels and its RNA expression are reduced in obesity and insuline resistance, and increasing adiponectin, improves insulin sensitivity. ( The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

• Chronic hyperglycemia increases circulating levels of inflammatory biomarkers such as IL-6 and tumor necrosis factor-α (TNF-α) which, as the major cytokines, initiate inflammatory responses and cause the production of CRP as an acute-phase reactant.
  A low-grade inflammation in type 2 diabetes mellitus play a major role in pathogenesis of its secondary complications such as atherothrombosis, nephropathy, retinopathy and cardiovascular disease.
  Ginger supplementation in oral administration reduced inflammation in type 2 diabetic patients. So it may be a good remedy to diminish the risk of some chronic complications of diabetes.
  Gingerols and shogaols reduce prostaglandin synthesis through suppression of cyclooxygenase- 1 and cyclooxygenase-2. Moreover, ginger suppresses leukotriene biosynthesis by inhibiting 5-lipoxygenase.
  It has been shown that the components of ginger are more effective than conventional non-steroidal anti-inflammatory drugs (NSAIDs) with fewer side effects. (Anti-inflammatory effects of zingiber officinale in type 2 diabetic patients, 2013)

• Ginger and its phytochemicals are also shown to decrease the levels of pro-inflammatory cytokines (TNFα, IL 1β, IL-6 and interferon-γ), to reduce the elevated expression of NFkβ (A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe), 2013) and to inhibit inducible nitric oxide synthase. ( The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus, 2014)

PROTECTIVE EFFECTS OF GINGER IN DIABETIC COMPLICATIONS

Ginger has protective effects on diabetic liver complications. in fact, ginger reduces the levels of IL6 and TNFα, reduces NFkβ activity and ROS products and increases LDL receptors. (Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review, 2012).
Moreover ginger has positive effects on diabetic kidney complications beacause reduces the level of malondialdehyde (MDA). Reactive oxygen species degrade polyunsaturated lipids, forming malondialdehyde. This compound is a reactive aldehyde and is one of the many reactive electrophile species that cause toxic stress in cells. The production of this aldehyde is used as a biomarker to measure the level of oxidative stress in an organism. ( The effect of ginger on diabetic nephropathy, plasma antioxidant capacity and lipid peroxidation in rats, 2007)