**6. The adverse reactions of CR**

on oxidative stress. CR results in an increase in the level and activation of \_adenine nucleotide translocase (ANT) and uncoupling protein (UCPs) to reduce the mitochondrial membrane potential, which induces a decrease in superoxide radical production at complex 1 of the electron transport chain. Less damage to the lipids in the mitochondrial membrane is further reduced by increases in the membrane lipid saturation. Increases in superoxide dismutase convert superoxide into hydrogen peroxide and increased levels of glutathione peroxidase (GPX) and catalase convert this to water reducing the product of the toxic hydroxyl radical (OH-) [26]. Lower levels of OH reduce the oxidative damage to proteins and DNA, which is further ameliorated by enhanced levels of degradation and base excision repair respectively. Animal experiments also confirmed that the oxygen free radicals in mice reduced and the βhydroxybutyrate, which could act as an antioxidant, was increased after CR. In some clinical studies, some inflammatory factors (such as tumor necrosis factor-α, interleukin-6, interleu‐

In 2011, Qiao et al. [27] found adiponectin gene expression increased in CR mice. Adiponectin in circulation could regulate various metabolic processes, including anti-inflammatory, insulin

sensitivity and resistance, et al. It becomes another possible mechanism.

kin-8) decreased significantly after CR.

190 Treatment of Type 2 Diabetes

**Figure 2.** The effects of calorie restriction on oxidative stress.

**4.4. Adiponectin**

Strict caloric restriction may increase risk of hypoglycemia. There are not enough evidences that CR causes arrhythmia or electrolyte disorders in the studies reported until now [29]. The risk of gallstones may be higher in the first few days because of inadequate intake of fat. Bone density decreases during CR without any data showing it increases fracture risk. The most remarkable adverse reaction is increase of uric acid during CR, but only few study found it induced gout. CR may induce the onset of ketosis, which may depend on the total intake of carbohydrate rather than calorie [30]. However, the level of ketone bodies in serum during CR is generally 0.33-0.71mmol/l, which is far below the level during ketoacidosis (>25mmol/l), even though it is abnormal.

Other possible adverse effects include mild dizziness, headache, fatigue, cold, dry skin, transient rash, changes of defecate habits, hair loss, cramps, menstrual disorders and shortterm elevated transaminases [31]. Yet for all that, these adverse effects are all slight, and can be treated easily. Generally, CR is relatively safe in patients with type 2 diabetes, but more long-term adverse effects needed to be observed.
