**3. The therapeutical effect of CR on T2DM**

#### **3.1. The short-term therapeutical effect of CR on T2DM**

CR has shown to be helpful for the blood glucose control and the improvement of pancreatic islet function. It produces multiple beneficial effects on metabolic parameters in type 2 diabetic patients by virtue of both calorie restriction and weight loss. Animal experiments confirmed that CR regulates the process of glucose metabolism in a variety of tissues (adipose tissue, liver, pancreas, skeletal muscle, et al) [7]. In clinical trials, the blood glucose of the participators decreased to normal range within a few days, and to the lowest point after 1-2 weeks [8]. In another short-term study of 14 obese patients with T2DM using VLCDs, marked improvement was seen in glycosylated HbA1c [9]. It fell from 7.4±0.3% to 6.0±0.2% after 8 weeks VLCD [10]. As a consequence, CR was thought to improve glucose metabolism in type 2 diabetics. Besides, the fasting plasma insulin/C-peptide levels of patients with T2DM fell after CR, and thus improved the insulin sensibility [11]. Generally, Blood pressure, triglycerides, total cholesterol and LDL-C were reduced, while only HDL-C varied [12, 13].

#### **3.2. The long-term therapeutical effect of CR on T2DM**

Whether CR improves the state of T2DM for a long time has been the major concern for many researchers. Unick et al. [14] chose 5145 type 2 diabetic patients randomized to an intensive lifestyle intervention and diabetes support and education. The lifestyle interven‐

tion group received a behavioral weight loss program that included group and individu‐ al meetings, a ≥10% weight loss goal, calorie restriction, and increased physical activity. Diabetes support and education received a less intense educational intervention.After four years follow-up, body weight, blood glucose and lipid profile improved significantly in the intervention group, suggesting that CR may obtain an optimal long-term metabolic control in T2DM patients.

Because of the poor compliance of patients with long-term CR, there are few researches in this area, and more researchers begin to concentrate on the long-term effect of short-term CR on T2DM patients. In a clinical study, 40 obese patients with T2DM and symptomatic hyperglycaemia were selected despite combination oral anti-diabetic therapy+/-insulin, and given 8 weeks of VLCD therapy (750kcal/d), followed by standard diet and exercise advice at 2-3 month intervals up to 1 year [15]. After 8 weeks of VLCD, body weight and body mass index (BMI) fell significantly, with favourable reductions in blood pressure, fructosa‐ mine and HbA1c. Sustained improvements were evident after 1 year, with minimal weight regain. Unexpectedly, glycemic control tended to deteriorate. In another study, 18 insulintreated T2DM patients were treated with 30 days VLCD (450kCal/day) with the cessation of all glucose-lowering medication, and then followed for 18 months [16]. Caloric intake was slowly increased to eucaloric and glucose-lowering medication can be restarted if necessary. After 18 months follow-up, the use of insulin was significantly reduced: 18 out of 18 patients on day 0, 5 out of 18 patients at 18 months. Moreover, although patients using insulin at 18 months had regained weight a little, but still had a better cardiovascu‐ lar risk profile compared with this parameter before CR (Table 1). In spite of favourable outcomes, these shorter term CR studies still require more data to clarify the long-term therapeutical effect of CR on metabolic disorders.

#### **3.3. The studies of special crowd for CR**

the blood glucose stably and reduce its morbidity, but the differences of the treatment efficacy

As a lifestyle intervention method, it is very important to make sure whether this thera‐ py can prevent T2DM from occurrence in the high risk persons. Tuomilehto et al. [5] had assigned 552 middle-aged, overweight subjects with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. After 3.2 years followup, they found that the cumulative incidence of diabetes was 11 percent (95% confidence interval, 6% to 15%) in the intervention group and 23% (95% confidence interval, 17% to 29%) in the control group, moreover, during the trial, the risk of diabetes was reduced by 58% (P<0.001) in the intervention group. The next year, another larger sample follow-up study focused on the lifestyle intervention on diabetes prevention, including CR, exercise, et al. Three years follow-up later, CR reduced the incidence by 58% (95% confidence interval, 48% to 66%), as compared with placebo [6]. These studies provided satisfactory evidences

CR has shown to be helpful for the blood glucose control and the improvement of pancreatic islet function. It produces multiple beneficial effects on metabolic parameters in type 2 diabetic patients by virtue of both calorie restriction and weight loss. Animal experiments confirmed that CR regulates the process of glucose metabolism in a variety of tissues (adipose tissue, liver, pancreas, skeletal muscle, et al) [7]. In clinical trials, the blood glucose of the participators decreased to normal range within a few days, and to the lowest point after 1-2 weeks [8]. In another short-term study of 14 obese patients with T2DM using VLCDs, marked improvement was seen in glycosylated HbA1c [9]. It fell from 7.4±0.3% to 6.0±0.2% after 8 weeks VLCD [10]. As a consequence, CR was thought to improve glucose metabolism in type 2 diabetics. Besides, the fasting plasma insulin/C-peptide levels of patients with T2DM fell after CR, and thus improved the insulin sensibility [11]. Generally, Blood pressure, triglycerides, total cholesterol

Whether CR improves the state of T2DM for a long time has been the major concern for many researchers. Unick et al. [14] chose 5145 type 2 diabetic patients randomized to an intensive lifestyle intervention and diabetes support and education. The lifestyle interven‐

among them are not clear until now.

186 Treatment of Type 2 Diabetes

**2. The preventive effect of CR on T2DM**

on the preventive effect of CR on T2DM.

**3. The therapeutical effect of CR on T2DM**

**3.1. The short-term therapeutical effect of CR on T2DM**

and LDL-C were reduced, while only HDL-C varied [12, 13].

**3.2. The long-term therapeutical effect of CR on T2DM**

Metabolic disorders including obesity and diabetes are more prevalent in children and adolescents. However, most of them cannot obtain a satisfactory blood glucose control since pharmacologic agents currently approved for use in children and adolescents with T2DM (metformin and insulin) are less optimal. Therefore, in hope of a better glucose control in children, lifestyle intervention attracted many interests. A chart review of 20 children (mean age 14.5±0.4 years) who consumed a ketogenic VLCD in the treatment of T2DM was conducted [17]. Eventually, VLCD allowed insulin and oral agents to be discontinued in all but one subject who was not compliant, and no other subjects required resumption of medications during the course of the diet on the condition that the metabolic parameters such as blood glucose and blood pressure were well controlled. More importantly, this study monitored the metabolic profiles to ensure that the patients were not at risk for developing electrolyte disturbances or ketoacidosis. Fortunately, none experienced nausea, vomiting, dehydration, or other side effects, such as orthostatic dizziness, muscle cramps, fatigue or halitosis previously reported in pediatric studies.

The efficacy and safety of CR in the elderly were also investigated. Recently, a total of 5145 individuals with T2DM (1053 aged 65 to 76 and 4092 aged 45 to 64) were chosen to compare the effects of 4 years of intensive lifestyle intervention in older and younger individuals [18]. Both groups were respectively divided into two subgroups and given either lifestyle inter‐ vention (include CR and exercise) or health education. After 4 years follow-up, lifestyle intervention was favourable to a better control of blood glucose, blood pressure. Surprisingly, the elderly group gained more benefits than the younger group. Therefore, CR may be considered to be a treatment to metabolic disorders.
