Effect on blood glucose

In the present study, we found no significant differences on any of the glycaemic outcome measures between the Jiangtang Xiaozhi and placebo groups at completion of the treatment. However, the study yielded three positive findings on secondary outcomes. First, levels of insulin resistance (HOMA-IR) were lower than those in the placebo group. Second, serum insulin slightly decreased in the treatment group compared to worsening levels in the placebo group, resulting in a borderline significant difference between groups. Third, HDL cholesterol was significantly improved in Jiangtang Xiaozhi group compared to the placebo. The absence of a detectable glycaemic measures in this trial contradicts with the previous clinical trial. In this earlier trial in a group with type 2 diabetes, plasma glucose levels reduced significantly from baseline after 8 weeks treatment by −1.71 ± 2.52 mmol/L compared to −0.72 ± 4.17 mmol/L in the pioglitazone group[9]. Postprandial plasma glucose and HbA1c also both showed a significant difference compared to baseline (11.41 ± 2.63 mmol/L to 9.91 ± 1.93 mmol/L and 7.35 ± 1.87% to 6.73 ± 1.02%, respectively). The reasons for this discrepancy can be complex. However, possible explanations may include: (a) this herbal medicine may be ineffective in treating elevated glucose levels in people with IGT; (b) it may be that the size of the sample was not sufficiently large to detect an effect, particularly given the transient nature of IGT; (c) an effect might only occur with greater symptom severity at baseline[19]. The fourth possibility is that the dosage of Jiangtang Xiaozhi was not adequate. Our clinical trial cohort was largely overweight and obese with a mean BMI of 30.8 kg/m2, which may also affect the efficacy of an intervention[20].

A significant improvement within the Jiangtang Xiaozhi group on postprandial plasma glucose levels at the completion of the treatment was identified compared to baseline. Measuring change from baseline is an acceptable and meaningful statistic where baseline levels are comparable between the intervention and placebo groups, which in our case they were. Hyperglycaemia in prediabetes is primarily postprandial in nature. The body is unable to control blood glucose adequately after a loading of ‘sugar’. It is these postprandial ‘spikes’ in blood glucose levels that are thought to be toxic to the beta-cells and cause them to dysfunction[21]. Perhaps Jiangtang Xiaozhi may be of assistance in reducing these ‘spikes’.

Effect on insulin

Insulin resistance is a decreased responsiveness of target tissues - skeletal and myocardial myocytes, hepatocytes, and adipocytes - to normal levels of circulating insulin (Setsi 2006). In our placebo group, higher levels of insulin resistance (HOMA-IR) accompanied higher levels of serum insulin. This is to be expected. Greater serum insulin levels are seen in those with higher insulin resistance. A smaller insulin response is anticipated in those with better insulin sensitivity. At week 16 of treatment, there was a trend for insulin resistance to improve in the Jiangtang Xiaozhi group compared to the placebo group, but the change narrowly missed statistical significance.

However, the level of change detected in insulin resistance in our trial may only have marginal clinical significance. Cut-off values for normal HOMA-IR are considered to lie somewhere between 2.5 and 4.1[17, 22, 23]. At these values our clinical trial cohort would be considered to be in the non-clinical range at the start of the trial with levels of 2.12 ± 1.30 and 1.60 ± 0.92 in the placebo and Jiangtang Xiaozhi groups respectively. The 3 month clinical trial of the herbal extract, berberine, found a clinical and statistically significant difference with HOMA-IR reducing from 3.9 to 2.44 in people with diabetes not IGT[24]. Perhaps our clinical trial cohort was overall too well at baseline and our sample did not allow for sufficient power to detect change from these baselines.

In the present study, mean beta-cell function (HOMA%B) increased in the placebo group from 87% to 99% but not to a statistically significant degree while remaining stable in the Jiangtang Xiaozhi group (82% to 84%). These results could be interpreted as a trend towards improvement in the beta-cell function of the placebo group. However, beta-cell function needs to be interpreted in the context of serum insulin, insulin sensitivity and insulin resistance.

Typically a beta-cell or HOMA%B value that is closer to 100% is associated with better beta-cell function[17, 25–27]. Why then in the placebo group, compared to the Jiangtang Xiaozhi group, would insulin secretion increase, insulin sensitivity decrease but beta-cell function (HOMA%B) appear to improve? One explanation may be that a ‘high’ HOMA%B does not always equate to better beta-cell functioning but perhaps the opposite.

When insulin sensitivity is improved, beta-cell activity may be reduced – the beta-cells of the pancreas simply don’t have to work as hard anymore[17]. This explanation is supported by several longitudinal studies which have shown that decreased beta-cell function as represented by HOMA%B does not, on its own, seem to predict the development of diabetes. A five year study of 12,924 non-diabetic Koreans examined the role of HOMA%B in predicting the development of diabetes. They found that the HOMA%B baseline value was actually higher in those who went on to develop diabetes[28]. Another study which utilised HOMA to predict the development of diabetes concluded that whereas low insulin secretion may be adequate for an insulin sensitive patient, the same level of beta-cell function may be inadequate for another patient[29]. The developers of the HOMA instrument have indeed pointed out that “HOMA-%B is a measure of beta-cell activity, not of beta-cell health or pathology” and that HOMA%B values need to be considered alongside HOMA%S and HOMA-IR[17]. Therefore what may have been happening in the placebo group was the natural progression of diabetes: an increase in insulin secretion combined with a rise in beta-cell activity (HOMA%B) coupled with a rise in insulin resistance (HOMA-IR) indicating that the beta-cells are working harder. Whereas in the Jiangtang Xiaozhi group the insulin measures, stable serum insulin, stable insulin sensitivity and reduced insulin resistance compared to the worsening insulin measure in the placebo group indicate that progression has perhaps stalled but not reversed.

Nonetheless, the degree to which the intervention appeared to maintain insulin sensitivity levels, restrain insulin secretion and thereby help preserve beta-cell function does warrant further investigation. Worsening of impaired glucose tolerance, progressing to frank diabetes is generally accepted as a consequence of insulin resistance, impaired insulin secretion and pancreatic beta-cell failure[30–32]. While the relative contribution of each of these factors is still a subject for debate, we do know that insulin resistance plays a key role and this is evidenced by a number of longitudinal and cross-sectional studies.

Effect on cholesterol

People with diabetes often have abnormally low levels of HDL cholesterol and high levels of triglycerides[33]. There is also a strong association between dyslipidaemia and insulin resistance[34]. We found that high-density lipoprotein cholesterol (HDL), otherwise known as the ‘good’ cholesterol, improved post-treatment in the Jiangtang Xiaozhi group compared to the placebo group. Cholesterol lowering medication was being taken by nearly all our clinical trial participants. When analysed as a covariant there was no significant effect exerted by cholesterol lowering medication consumption on any of the lipid results.

The mean post-treatment increase of 0.10 mmol/L in HDL-cholesterol in the Jiangtang Xiaozhi group represents a 6% change from baseline and is thus of some clinical significance. In a pooled analysis of four clinical trials of statins, individuals with a ≥7.5% increase in HDL cholesterol in conjunction with lowered LDL had a reduced incidence of coronary atherosclerosis[35].

A new approach toward treating dyslipidaemia alongside high blood glucose levels has been to target insulin resistance[36]. Thus, a possible explanation for the improved HDL levels in the Jiangtang Xiaozhi group may have been improved insulin resistance. Our results indicate Jiangtang Xiaozhi both improves HDL levels and stabilises insulin. This is a particularly encouraging clinically relevant finding as it signifies the potential of the Jiangtang Xiaozhi to treat two conditions and thus avoid some of the problems inherent with polypharmacy.

Limitations of our study

Our study has several limitations. Firstly, our sample size may have lacked sufficient statistical power to detect a clinically significant change in FBG and to adequately account for the transient nature of people with IGT[19]. Secondly, the intervention period may have been too short to allow for the natural progression of impaired glucose tolerance. A further limitation relates to the methodology of the outcome measures. We used HOMA to assess insulin resistance and sensitivity as a cost effective method with validity for clinical trials. The use of the euglycaemic clamp method to assess insulin sensitivity may have provided a more accurate result. Clamp methods are not feasible in large studies. Likewise we used only one insulin measure and this may not have sufficiently accounted for intra-individual variation. A final limitation was dosage. The dosage used in our trial was significantly less than that used in the trial of Jiangtang Xiaozhi in people with diabetes (34 grams per day compared to 75 grams per day in the first study). It is also likely that therapeutic doses weren’t reached by some participants. The regime of three tablets three times a day is a difficult dosage regime. Although a final pill count was undertaken not all participants returned leftover medication. Simpler, less frequent dosing regimens result in better compliance[37].

In summary, although Jiangtang Xiaozhi did not significantly change blood glucose levels, the intervention was associated with some positive effect on insulin and HDL. The positive results of Jiangtang Xiaozhi in reducing postprandial glucose indicate that a higher level of baseline severity in blood glucose symptoms might yield more reliable findings. Our analysis was considerably underpowered. A longer study, in line with other interventions in this population group, to allow for the natural progression of the disease may also bring forth an effect on fasting blood glucose. The strength of this study was that it was a robust double-blinded, placebo controlled trial conducted according to rigorous scientific methodology.

The safety of this herbal formulation and its components has been demonstrated in animal and human studies. The lack of, or minimal, side effects provide a considerable advantage over many of the current pharmaceutical treatments used for the treatment of prediabetes and controlled diabetes.

In light of the growing epidemic of diabetes worldwide, preventing or delaying the onset of diabetes may likewise reduce the microvascular and macrovascular complications of the disease. It is worthwhile investigating the potential of Jiangtang Xiaozhi to decrease blood glucose levels and reduce or prevent the incidence of diabetes in a longer, adequately powered trial.