Clinical Report

A randomised single blind parallel group study on efficacy, safety and tolerability of thrice daily “SeriCha” ingestion for 8 weeks in comparison with Green Tea in 30 subjects in with type 2 Diabetes Mellitus.

NR Deshpande, SD Aman, RS Parmaj
Belgaum Diabetes Centre, Maruti Galli, Belgaum 590001

PREAMBLE

Type 2 diabetes is a non-communicable disease that has assumed epidemic proportions in recent times. Diabetes is largely classified as a lifestyle disease and most actions to reduce prevalence are focused primarily on lifestyle management. However, this is an onerous task and it appears that a middle path may have greater patient compliance than merely lifestyle management. This would involve healthy lifestyle practices combined with administration of dietary supplements known to favorably affect carbohydrate/insulin metabolism. This may not only delay and or prevent the onset of diabetes but may also complement well-established anti-hyperglycemic therapies used to treat known diabetics.
 To this end, mulberry leaves offer an exciting option. The use of the leaves as a therapeutic in its own right and as an addition to other food products to reduce their potential for inducing hyperglycemia  have been studied, with very promising results. Additionally, the presence of polyphenols and flavonoids in mulberry leaves show potential for anti-oxidant activity, a therapeutic bonus in diabetes, given the role of oxidative stress in potentiating occurrence of diabetic complications.

HISTORY OF MULBERRY LEAVES

The use of mulberry leaves, a foliage to silk worms, as a food supplement is not a new concept. Mulberry has been used in Chinese medicine since 659 AD. The virtues of mulberry have been extolled in “Book of Songs” written in 1000 BC in Southeast Asia. In the “Compendium of Materia Medica”, written in the late 1500s, Li Si Zhin recommends leaves of white mulberry for treatment of diabetes and obesity. These concepts are being revisited in recent times. M. alba (white mulberry) has been used in traditional medicines. It has been shown that it contains high quality proteins and has been known to improve the quality of wheat flour when mixed with it1
The micronutrient composition of the leaves has also been elucidated and found to contain many vitamins or their precursors2.Notable among them are ascorbic acid, B carotenes, iron, zinc, calcium and magnesium. The flavanones present in them are said to have antimicrobial activity.

MULBERRY LEAVES IN DIABETES

The presence of DNJ-deoxynojirimycin- a potent alpha glucosidase inhibitor in mulberry leaves confers anti-hyperglycemic properties on it3. DNJ is an imminosugar- a carbohydrate mimic closely resembling monosaccharide. In the intestine, 1-DNJ shows competitive inhibition by binding with alpha glucosidase thereby significantly reducing the breakdown of carbohydrate to glucose and slowing its entry into the circulation.  It has been postulated that mulberry leaves work in a variety of ways to help treat diabetes4:

  • Reduction in absorption of glucose owing to alpha glucosidase inhibitor activity
  • Increase in insulin levels - needs a further validation through clinical studies
  • Anti-oxidant properties
  • Reduction in subsequent food intake, thereby helping to control dietary irregularities in diabetes.

Several studies to substantiate the above statements have been conducted to date. Kimura et al (2007)5 showed that a single oral dose of 0.8 and 1.2 g of DNJ enriched powder significantly reduced the post prandial blood glucose while increasing insulin secretion. Hansawasdi and Kawabata (2006)6 demonstrated that 1 gm of mulberry tea when heated for 3-5 minutes in 100 ml of water at 980C could inhibit various enzymes such as alpha glucosidase, sucrase and maltase. Asano et al (2001)7 have suggested that potentially, both diabetes and obesity could be prevented using natural dietary supplements containing 1-DNJ and other AGIs in high concentration.

ANTI-OXIDANT VALUE OF MULBERRY LEAVES

The leaves of M.alba contain phenolic compounds such as flavonoids, prenylflavanes and prenylflavane glycoside8. These compounds possess anti-oxidant activity. The flavonoid, Quercetin 3 (6-malonyl glucoside), is particularly important in this regard. In fact, the water extract of M.alba leaves have very high anti-oxidant properties that can scavenge hydroxyl radicals9. The ethanolic extract of the same can scavenge superoxide. This property has significance because mulberry leaves have been known to improve levels of glutathione and reduce catalase activity. This helps to inhibit LDL oxidation10.

STUDY DESIGN AND METHODS

A single blind randomized study was designed and conducted comparing SeriCha (SC) to commercially available green tea (GT) using a  random number table for parallel grouping. SeriCha drink made from mulberry leaves is hygienically packed in sachets and is free from caffeine, heavy metals, preservatives, pesticides and artificial flavors. GT used was a commercially available brand.

The study population consisted of type 2 diabetic patients (n=30) with a disease duration of less than 5 years.
The existing background therapy was noted and remained stable throughout the study. At entry into the study, detailed medical history was recorded and complete physical examination was conducted with vitals and anthropometric measurements. Baseline HbA1c, lipids and blood sugars were measured. Subjects were followed up every fortnight for 2 months and monitored for any adverse events, blood sugar levels, vitals, etc. Compliance to treatment was checked and ensured at every follow-up visit. At the last visit, anthropometry, vitals and laboratory parameters such as HbA1c, lipids and blood sugars were evaluated again. Other safety parameters such as liver enzymes and creatinine were monitored.

RESULTS

All the results presented are a comparison of effects from baseline to end of treatment (EOT) within each group.

  • FBS reduction: 18.9 % in SC group (p 0.0009) Vs 7.01% in GT group (p 0.09)
  • PPBS reduction: 18.1% in SC group (p 0.024) and 18.2% in GT group (p 0.023)

  • Percentage of subjects with FBS reduction:  92% in SC group had a mean FBS reduction of 56.4 %, i.e., 29.4 mg%, from baseline to EOT (p 0.003) whereas 70 % subjects in GT group had 58.8 % reduction (28.1 mg %) (p 0.009).
  • Percentage of subjects with PPBS reduction: 84.6 % in SC group had a mean PPBS reduction of 132.5 %, i.e., 64.7 mg%, from baseline to EOT (p 0.0005) whereas 70 % subjects in GT group had 115 % reduction (49.8 mg %) (p 0.0001).
  • HbA1c reduction: In the SC group the reduction from baseline to EOT was 0.5 % (p 0.028) whereas it was 0.1 % in the GT group (p 0.22).

  • HDL: No statistically significant change in either group from baseline to EOT.
  • LDL: Modestly significant decrease in GT group and no change in SC group.
  • Total cholesterol: Reduction in both groups, but slightly more significant in GT group.
  • Triglycerides: No change in either group.
  • SGOT: Significant reduction (p 0.02) in SC group compared to GT group (0.62).
  • SGPT: Reduction in both groups, but not significant.
  • Serum creatinine: No change in either group.
  • Systolic BP: Very modest reduction in SC group, but not significant.
  • Diastolic BP: Reduction in both groups, but not significant.
  • Anthropometry: No change in either group with respect to weight/BMI or body fat percent.

No significant adverse events were observed in either group or none that could be related to either SeriCha or Green tea. All patients completed the study with good compliance.

DISCUSSION

In this study, SeriCha drink made from mulberry leaves was used as a supplementary add-on to existing anti-hyperglycemic therapy with the objective of improving glycemic status without having to increase the dose of existing therapy in type 2 diabetic individuals. Since most patients are averse to increasing tablets for better control as seen in routine practice, drinking “tea” thrice daily was easily accepted by the subjects and therefore compliance was not an issue.
Subjects with duration of diabetes less than 5 years were selected to maintain uniformity and also because SeriCha is expected to have good activity in patients who still have moderate endogenous insulin reserves. Green tea was chosen as a comparator as its therapeutic potential, although not fully proven, has been studied in the past, and would be acceptable to the subject population.

The FBS reduction seen with SeriCha at the end of the study was very significant and much higher than that seen for GT (18.9 % vs. 7.01%). Not only was the mean FPG reduction substantial, but also the proportion of patients achieving it. It was seen that 92 % of the patients in Sericha group achieved a mean reduction of 56 mg% whereas only 70% of the GT group could achieve a similar reduction. These findings were quite surprising considering that most evidence points to mulberry leaves having alpha glucosidase activity that would expect it to have predominantly prandial glucose reduction. There is then a possibility that Sericha could possess some insulin secretogogue activity as well. This would of course have to be borne out in larger studies with more sophisticated tests of insulin secretion.

As expected, owing to its known alpha glucosidase activity, the SeriCha group demonstrated prandial glucose reduction that was as significant as the FBS reduction. A similar reduction was seen in the comparator GT group. However, it is notable that a higher proportion of patients in the SeriCha group (84.6%) achieved this reduction than in the GT group (70%). Moreover the reduction achieved in the SeriCha group was higher (64.7 mg %) than in the GT group (49.8 mg %). This signifies that SeriCha is a superior prandial glucose regulator as compared to the comparator, Green Tea
Not surprisingly, the effect of SeriCha on HbA1c was superior to that of the comparator Green Tea on account of a superior effect on both FBS and PPBS (O.5% Vs 0.1%). This reduction is similar to many of the existing anti-hyperglycemic therapies. Evidently, SeriCha appears to be a viable option in the armamentarium of anti hyperglycemic therapies and one that is quite safe going by its adverse event profile.

Neither group demonstrated any significant change in lipid profile at the end of the study. Perhaps, longer studies with more patients could throw more light on this issue.

The significant reduction of SGOT in the SeriCha group points to a favorable effect on insulin resistance, although it may be too premature to make a definitive claim. Further studies in this direction are definitely warranted.
As can be seen in the results of all safety parameters, SeriCha appears to be safe. The adverse events are minimal and unrelated to Sericha.

CONCLUSIONS

SeriCha, a caffeine free drink prepared from mulberry leaves, is a viable option in type 2 diabetes patients that is acceptable, palatable and devoid of any significant side effects. Good overall glycemic control and a possible favorable effect on insulin resistance make it an option not only for diabetic individuals, but also as a possible agent for individuals at high risk of developing diabetes.

REFERENCES

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