Therapeutic Applications of Plant and Nutraceutical-Based Compounds for the Management of Type 2 Diabetes Mellitus: A Narrative Review.

Diabetes mellitus is a condition caused by a deficiency in insulin production or sensitivity that is defined by persistent hyperglycemia as well as disturbances in glucose, lipid, and protein metabolism. Uncurbed diabetes or incessant hyperglycemic condition can lead to severe complications, including renal damage, visual impairment, cardiovascular disease, neuropathy, etc., which promotes diabetes-associated morbidity and mortality rates. The therapeutic management of diabetes includes conventional medications and nutraceuticals as complementary therapies. Nutraceuticals are bioactive compounds derived from food sources that have health-promoting properties and are instrumental in the management and treatment of various maladies. Nutraceuticals are clinically exploited to tackle DM pathogenesis, and the clinical evidence suggests that nutraceuticals can modulate biochemical parameters related to diabetes pathogenesis and comorbidities. Hypoglycemic medicines are designed to mitigate DM in traditional medicinal practice. This review intends to emphasize and comment on the various therapeutic strategies available to manage this chronic condition, conventional drugs, and the potential role of nutraceuticals in managing the complexity of the disease and reducing the risk of complications. In contrast to conventional antihyperglycemic drugs, nutraceutical supplements offer a higher efficacy and lesser adverse effects. To substantiate the efficacy and safety of various functional foods in conjunction with conventional hypoglycemic medicines, additional data from clinical studies are required.

Estimating the Unit Costs of Healthcare Service Delivery in India: Addressing Information Gaps for Price Setting and Health Technology Assessment.

BACKGROUND: India's flagship National Health insurance programme (AB-PMJAY) requires accurate cost information for evidence-based decision-making, strategic purchasing of health services and setting reimbursement rates. To address the challenge of limited health service cost data, this study used econometric methods to identify determinants of cost and estimate unit costs for each Indian state. METHODS: Using data from 81 facilities in six states, models were developed for inpatient and outpatient services at primary and secondary level public health facilities. A best-fit unit cost function was identified using guided stepwise regression and combined with data on health service infrastructure and utilisation to predict state-level unit costs. RESULTS: Health service utilisation had the greatest influence on unit cost, while number of beds, facility level and the state were also good predictors. For district hospitals, predicted cost per inpatient admission ranged from 1028 (313-3429) Indian Rupees (INR) to 4499 (1451-14,159) INR and cost per outpatient visit ranged from 91 (44-196) INR to 657 (339-1337) INR, across the states. For community healthcare centres and primary healthcare centres, cost per admission ranged from 412 (148-1151) INR to 3677 (1359-10,055) INR and cost per outpatient visit ranged from 96 (50-187) INR to 429 (217-844) INR. CONCLUSION: This is the first time cost estimates for inpatient admissions and outpatient visits for all states have been estimated using standardised data. The model demonstrates the usefulness of such an approach in the Indian context to help inform health technology assessment, budgeting and forecasting, as well as differential pricing, and could be applied to similar country contexts where cost data are limited.

Dietary supplementation of Ashwagandha (Withania somnifera, Dunal) enhances NK cell function in ovarian tumors in the laying hen model of spontaneous ovarian cancer.

PROBLEM: Ovarian cancer (OVCA) disseminates in a distinct pattern through peritoneal metastasis and little is known about the immunosuppression in the tumor microenvironment. Our goal was to determine changes in NK cell population during OVCA development and the effects of Ashwagandha (Withania somnifera, Dunal) supplementation on NK cell localization in laying hens with OVCA. METHODS: Frequency of NK cells in ovarian tumors at early and late stages in 3- to 4-year-old hens (exploratory study) as well as in hens supplemented with dietary Ashwagandha root powder for 90 days (prospective study) was examined. RESULTS: The population of stromal NK cells but not the intratumoral NK cells increased with OVCA development and progression. Ashwagandha supplementation decreased the incidence and progression of OVCA. Both the stromal and intratumoral NK cell population increased significantly (P < 0.0001) in Ashwagandha supplementated hens. CONCLUSION: The results of this study suggest that the population of stromal and tumorinfiltrating NK cells is increased by dietary Ashwagandha supplementation. Thus, Ashwagandha may enhance antitumor function of NK cells. This study may be useful for a clinical study to determine the effects of dietary Ashwagandha on NK cell immune function in patients with ovarian cancer.

Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type-2 diabetes.

In the present study, resveratrol, a polyphenolic SIRT1 activator was evaluated for its SIRT1 activation in an in vitro fluorescent based assay (EC(50) : 7 µM). The efficacy of resveratrol was also evaluated in ob/ob mice for its antidiabetic and associated metabolic effects. Mice aged 5-8 weeks were included in four groups; control and resveratrol at 5, 15, 50 mg/kg, b.i.d. and were dosed orally. After 4 weeks of drug treatment, body weights were noted and random blood glucose and insulin was estimated for the antidiabetic effect. Animals were also subjected to the oral glucose tolerance test to observe any improvement in the glucose excursion. Triglycerides, total cholesterol, adiponectin and free fatty acid levels were also estimated. The results showed that resveratrol exhibited significant antihyperglycemic activity with an improvement in the insulin levels compared with the control mice. There was also a significant improvement observed in the glucose excursion in the oral glucose tolerance test performed for 120 min; although an insignificant improvement in the triglycerides, total cholesterol, adiponectin and free fatty acid levels was observed at different doses of resveratrol tested. The present findings suggest that resveratrol is an antihyperglycemic agent and drugs similar to resveratrol can be considered as an effective therapeutic adjuvant for the current treatment of diabetes mellitus.

Evaluation of hypoglycemic and anti-hyperglycemic potential of Tridax procumbens (Linn.).

BACKGROUND: Diabetes is a metabolic disorder affecting carbohydrate, fat and protein metabolism. Tridax procumbens Linn. (Family-Asteraceae; common name-Dhaman grass) is common herb found in India. Traditionally, the tribal inhabitants of Udaipur district in Rajasthan (India) uses the leaf powder (along with other herb) orally to treat diabetes. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's application in traditional medicine system. METHODS: Extraction of whole plant of T. procumbens using 50%methanol. The extract was tested for acute and sub-chronic anti-hyperglycemic activity in alloxan induced diabetic rats and for acute toxicity test among normal rats. Observations on body weight as well as on the oral glucose tolerance levels were also recorded. RESULTS: Oral administration of acute and sub chronic doses (250 and 500 mg/kg b.wt.) of T. procumbens extract showed a significant (p < 0.05) reduction in fasting blood glucose levels in diabetic rats, however the decline in blood sugar levels in normal rats was not observed. In acute study the maximum percent blood glucose reduction (68.26% at 250 mg/kg and 71.03% at 500 mg/kg body weight) in diabetic rats was observed at 6 h. The anti-hyperglycemic effects were not dependent of dose and the OGTT and Body weight supported the antihyperglycemic action of the drug. The results of anti-diabetic effect of T. procumbens were compared with the reference standard drug Glibenclamide (10 mg/kg b.wt.). CONCLUSION: These test results support traditional medicinal use of, T. procumbens for the treatment of diabetes mellitus with corrections in body weight and oral glucose tolerance and no visible signs or symptoms of toxicity in normal rats indicating a high margin of safety. These results warrant follow-up through bioassay-directed isolation of the active principles.

Curcumin potentiates the anti-inflammatory activity of cyclooxygenase inhibitors in the cotton pellet granuloma pouch model.

Curcumin is a yellow-colored plant polyphenol with a long history of medicinal use in ayurvedic, Chinese and Japanese medicine. Studies have reported the cyclooxygenase COX-2-inhibitory activity of this polyphenol; however, none of the studies have established its antiinflammatory activity in the rat cotton pellet granuloma pouch model, which mimics subchronic inflammation in humans. The present study was conducted to evaluate the effect of curcumin in the cotton pellet granuloma pouch model. Furthermore, the interaction of curcumin with standard anti-inflammatory drugs at subeffective doses was studied to evaluate its potential role as adjuvant therapy. Administration of curcumin (240 mg/kg i.p.), aspirin (160 mg/kg i.p.) or rofecoxib (5 mg/kg i.p.) for 6 days in the cotton pellet granuloma pouch test exhibited significant anti-inflammatory activity, as demonstrated by a decrease in both dry and wet weights of the cotton pellet as compared to the control animals. Lower doses of curcumin (120 mg/kg i.p.), aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) were ineffective. However, the combination of a subeffective dose of curcumin (120 mg/kg i.p.) with submaximal doses of aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) produced a synergistic effect. Furthermore, there was marked increase in tumor necrosis factor-alpha (TNF-alpha) levels (estimated by enzyme-linked immunosorbent assay, ELISA) in the serum of the animals implanted with cotton pellets presenting marked inflammatory events. Daily administration of curcumin, aspirin or rofecoxib decreased the levels of TNF-alpha, further demonstrating anti-inflammatory activity. Curcumin in combination with aspirin or rofecoxib caused a further decrease in serum TNF-alpha levels. In conclusion, the results of the present study demonstrate an anti-inflammatory effect for curcumin in the cotton pellet granuloma pouch test, possibly acting through COX enzyme inhibition, and further inhibiting the generation of inflammatory mediators such as TNF-alpha. These results point toward the usefulness of curcumin as adjuvant drug therapy along with standard anti-inflammatory drugs.

Lycopene attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain.

Diabetic neuropathic pain, an important microvascular complication of diabetes mellitus is recognized as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of lycopene and its effect on tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) release in streptozotocin induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia alongwith increased plasma glucose and decreased body weights as compared with control mice. Lycopene (1, 2 and 4 mg/kg body weight; per oral) treatment, from the 4th to 8th week after streptozotocin injection, significantly attenuated thermal hyperalgesia and the hot-plate latencies. Lycopene also inhibited the TNF-alpha and NO release in a dose dependent manner. These results indicate an antinociceptive activity of lycopene possibly through its inhibitory action on NO and TNF-alpha release and point towards its potential to attenuate diabetic neuropathic pain.

Long-term subjective continence status and use of alternative treatments by women with stress urinary incontinence after collagen injection therapy.

This study examined subjective continence status and use of subsequent alternative therapeutic procedures at long-term follow-up after collagen injection for stress incontinence (SI) in women. Seventy women who underwent collagen injection for SI were identified by retrospective chart review and surveyed by mail questionnaire for subjective continence status, daily pad usage pre- and post-treatment, and use of anticholinergics and alternative procedures. Questionnaire responders' versus non-responders' mean age, follow-up, and pad usage were compared. Thirty-three women (47%) responded on questionnaires. Of the 33, 50% were dry or subjectively improved at long-term follow-up and 91% had not chosen an alternative invasive treatment after collagen injection. Chart review showed responders were not significantly different from non-responders in mean age (65.9 vs. 69.2 years), pad usage (0.6 vs. 0.8 pads/day), or follow-up (4.5 vs. 4.3 years). Collagen injection, a minimally invasive treatment for SI, appears to benefit a significant number of women.

Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha.

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognized as one of the most difficult types of pain to treat. The underlying mechanisms of painful symptoms may be closely associated with hyperglycaemia but a lack of the understanding of its proper aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of insulin and its combinations with resveratrol and curcumin in attenuating diabetic neuropathic pain. The study also aimed to examine the effect of these combinations on tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) levels in streptozotocin (STZ) induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose and decreased body weights compared with control mice. Chronic treatment with insulin (10 IU/kg/day, s.c.) and its combinations with antioxidants (resveratrol 20 mg/kg or curcumin 60 mg/kg, p.o.) for 4 weeks starting from the 4th week of STZ injection significantly attenuated thermal hyperalgesia and the hot-plate latencies. There was a significant inhibition of TNF-alpha and NO levels when these drugs were given in combination compared with their effects per se. These results indicate an antinociceptive activity of resveratrol and curcumin and point towards the beneficial effect of these combinations with insulin in attenuating diabetic neuropathic pain, possibly through the participation of NO and TNF-alpha.

Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats.

Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin.

Resveratrol, a polyphenolic phytoalexin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats.

The effects of resveratrol, a polyphenolic phytoalexin present in red wine have been investigated on hyperalgesia and cold allodynia in streptozotocin (STZ) induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (65mg/kg). After 4-weeks of STZ injection, diabetic rats exhibited a significant thermal hyperalgesia and cold allodynia along with increased plasma glucose and decreased body weights as compared with controls rats. Chronic treatment with resveratrol (10mg/kg orally) from week 4 to week 6 significantly attenuated the cold allodynia and thermal hyperalgesia. The results emphasize the role of oxidative stress in development of hyperalgesia and cold allodynia in diabetic animals and point towards the potential of resveratrol as an adjuvant therapy for the prevention and treatment of diabetic neuropathy.

Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats.

Diabetic nephropathy is a serious microvascular complication and one of the main causes of end-stage renal disease. Various studies have revealed that increased oxidative stress is a major pathophysiological mechanism which is involved in the etiology of diabetic nephropathy. Resveratrol, a polyphenolic phytoalexin present in red wine, is known to possess potent antioxidant properties and thus we aimed to examine its effect on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. After 4 weeks of STZ injection, rats were divided into four groups: the control rats, diabetic rats and diabetic rats treated with resveratrol (5 and 10 mg/kg, orally) respectively from week 4 up till week 6. At the termination of the experiments, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. The levels of the renal oxidative stress markers malonaldehyde and glutathione and the antioxidant enzymes superoxide dismutase and catalase were measured in kidney homogenate. STZ-injected rats showed significant increases in blood glucose, polyuria, proteinuria and a decrease in body weight compared with age-matched control rats. After 6 weeks, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance, and proteinuria along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key antioxidant enzymes. Treatment with resveratrol significantly attenuated renal dysfunction and oxidative stress in diabetic rats. The present study reinforces the important role of oxidative stress in diabetic kidney and points towards the possible antioxidative mechanism being responsible for the renoprotective action of resveratrol.