J Nutr Sci Vitaminol (Tokyo). 2001 Feb;47(1):57-63.

Maitake (Grifola frondosa) improve glucose tolerance of experimental diabetic rats.

Horio H, Ohtsuru M.

Department of Food Science and Nutrition, Faculty of Home Economics, Nishikyushu University, Saga, Japan.

We have previously reported that rats with diabetes induced by injecting streptozotocin into neonates showed remarkably lower blood glucose, urine volume, and glucosuria after administration of Maitake (Grifola frondosa). In the present study, we investigated the effects of Maitake on insulin concentration, organ weight, serum composition, and islets of Langerhans in streptozotocin-induced diabetic rats using the same method. The diabetic rats were produced by injecting 80 mg/kg B.W

. streptozotocin into 2-d-old neonates. From the age of 9 wk, the rats were given experimental diets for 100 d. The diabetes and control groups were given either diets containing 20% Maitake (DM and CM groups) or control diets (D and C groups). During administration of the experimental diets, we measured body weight, food intake, amount of feces, and serum insulin concentration at glucose loading. The glucose tolerance test was performed at the 10th week after the start of the experimental diets. The D group had an initial fasting blood glucose of 225+/-49 mg/dL, and a maximum blood glucose of 419+/-55 mg/dL at 60 min. In the DM group, however, the initial fasting blood glucose was 170+/-23 mg/dL, and the maximum blood glucose was 250+/-41 mg/dL at 15 min. Both values were markedly lower than those in the D group (p<0.05). The insulin concentration at 15 min. after glucose loading in the DM group was 41+/-16 microU/mL, which was significantly higher than that in the D group (15+/-7 microU/mL) (p<0.05). After the 100-d experimental period, blood samples were collected. The fructosamine level was significantly lower in the DM group (152+/-21 mmol/L) than in the D group (185+/-13 mmol/L). The concentration of 1.5-A.G. (1.5-anhydro glucitol) was significantly higher in the DM group (9.33+/-2.42 microg/mL) than in the D group (1.33+/-0.52 microg/mL). Observation of insulin antibody stain in the Langerhans cells of the pancreas using ABC method showed a decrease insulin antibody stain in the D group. The cells of the DM group were stained more darkly than those of the D group. From these results, we postulated that the bioactive substances present in Maitake can ameliorate the symptoms of diabetes.

PMID: 11349892 [PubMed - indexed for MEDLINE]

 

Diabetes, Obesity and Metabolism
Volume 4 Issue 1 Page 43 - January 2002
doi:10.1046/j.1463-1326.2002.00180.x

Effects of a water soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice

V. Manohar, N. A. Talpur, B. W. Echard, S. Lieberman and H. G. Preuss

Aim: We examined benefits of a water soluble extract of maitake mushroom designated as Fraction X (FXM) on the glucose/insulin metabolism of insulin resistant KK mice, and compared the results of FXM with those of a sulphonylurea, Glipizide.

Design: In several acute studies, insulin resistant KK mice were gavaged with a single dose of varying concentrations of FXM, or a single dose of one concentration of the oral hypoglycaemic drug, Glipizide. In the one chronic study, KK mice were gavaged with FXM, Glipizide, or an equal volume of isotonic saline (baseline control) twice daily. Retro orbital blood was drawn on the morning of the 4th and 7th days before the early gavage. Blood glucose was measured by routine laboratory procedures, and serum insulin was estimated by a radioimmunoassay (RIA) assay developed specifically for rodents.

Results: At a dose of FXM (140 mg/mouse), a statistically significant lowering of circulating glucose concentrations was again seen at 8 12 h and 16 18 h after oral gavage. The lowering approximated 25% of the original concentration. Oral gavage of Glipizide resulted in statistically significantly lower values of circulating glucose (25 37% lower compared with baseline) at 8 24 h post dosing. In the chronic study, the circulating concentrations of glucose and insulin of mice taking 140 mg FXM per day were decreased significantly at days 4 and 7.

Conclusions: FXM, a natural extract obtained from maitake mushroom, favourably influences glucose/insulin metabolism in insulin resistant KK mice. The lowering of both circulating glucose and insulin concentrations suggests that FXM works primarily by enhancing peripheral insulin sensitivity.

 

Biosci Biotechnol Biochem. 2004 Nov;68(11):2257-64. Related Articles, Links

Improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats.

Choi SB, Park CH, Choi MK, Jun DW, Park S.

Internal Medicine, KonKuk University, ChungBuk-Do, Korea.

The effect of supplementation with Phellinus linteus (P. linteus), Paecilomyces tenuipes (P. tenuipes), and Cordyceps militaris (C. militaris) mushroom water extracts on the insulin secretion and insulin resistance of 90% pancreatectomized (Px) male Sprague Dawley rats was investigated. Px rats were daily administered 0.5 g of P. linteus, P. tenuipes, and C. militaris aqueous extracts or a placebo per 1 kg body weight with a 40% fat diet for 8 weeks. Fasting serum glucose levels were lower in rats receiving C. militaris than in the control group. Insulin secretion at the elevated serum glucose levels was lowest in rats that consumed P. tenuipes in hyperglycemic clamp. Whole body glucose disposal rates increased in C. militaris but decreased in P. tenuipes compared to those in the control group in euglycemic hyperinsulinemic clamp. The GLUT4 content and fraction velocity of glycogen synthase in the soleus and quadriceps muscles increased in the rats treated with C. militaris, but P. tenuipes decreased both. In sum, a water extract of C. militaris ameliorates insulin resistance by enhancing glucose utilization in skeletal muscles.

PMID: 15564662 [PubMed - in process]

 

Life Sci. 2004 Apr 23;74(23):2897-908.

The anti-hyperglycemic activity of the fruiting body of Cordyceps in diabetic rats induced by nicotinamide and streptozotocin.

Lo HC, Tu ST, Lin KC, Lin SC.

Department of Bioscience technology, Chang-Jung Christian University, Tainan, 711, Taiwan.

Little scientific evidence exists to support the numerous herbs used to improve diabetes-related metabolic disorders. Cordyceps, a Chinese herbal medicine with fruiting body and carcass, has been proposed to have multiple medicinal activities. The objective of this study was to investigate the effects of fruiting body and carcass of Cordyceps on hyperglycemia. Male Wistar rats administered with placebo (STZ group), 1 g of fruiting body (FB group), 1 g of carcass (CC group), or 1g of fruiting body plus carcass (CF group) of Cordyceps for four weeks (d1 to d28) were injected with nicotinamide (200 mg/kg) and streptozotocin (65 mg/kg) on d15. Animals fed with placebo and injected with saline acted as the controls (CON group). The results showed that water intake (d15 to d29), changes in fasting blood glucose concentration (d15 to d26), and serum concentrations of fructosamine (d29) were significantly greater in the STZ, CC and CF groups than in the CON and FB groups (one-way ANOVA, P < 0.05). The diabetic rats had significantly lower weight gain and higher blood glucose response in oral glucose tolerance test than the control rats; and these changes were significantly reduced by administrating the fruiting body of Cordyceps. Our results revealed that fruiting body, not carcass, of Cordyceps attenuated the diabetes-induced weight loss, polydipsia and hyperglycemia, and these improvements suggest that fruiting body of Cordyceps has a potential to be the functional food for diabetes.

PMID: 15050427 [PubMed - indexed for MEDLINE]

 

Hepatobiliary Pancreat Dis Int. 2004 Feb;3(1):99-101. Related Articles, Links

Dynamical influence of Cordyceps sinensis on the activity of hepatic insulinase of experimental liver cirrhosis.

Zhang X, Liu YK, Shen W, Shen DM.

Department of Gastroenterology, Second Affiliated Hospital, Chongqing University of Medical Sciences, Chongqing 400010, China. sunnyzhangx@yahoo.com.cn

BACKGROUND: Cordeceps sinensis (CS) is a herb which can inhibit the liver fibrosis. Hyperinsulinemia is common in liver cirrhosis patients. The activity of insulin degrading enzyme could reflect the metabolism of insulin. This study was to detect the dynamical effects and mechanisms of CS on the activity of hepatic insulinase in CCl4 induced liver cirrhosis in rats. METHODS: Rats were randomly allocated into three groups: normal group, model group and CS group. The rats in the normal group were sacrificed at the beginning of experiment, and the other two groups were sacrificed randomly at the end of the third, sixth and ninth weeks. Blood and tissue specimens were taken. Biochemical assays were used to determine the changes of alanine transaminase (ALT), albumin levels in serum. And radioimmunological assays were used to determine the changes of hyaluronic acid (HA), insulin levels in serum and the activity of hepatic insulinase. RESULTS: No significant differences were seen in the serum levels of ALT, albumin, HA between the CS group and the model group at the third and sixth weeks (P>0.05). The serum levels of ALT, HA in the CS group were lower than those in the model group at the ninth week (P<0.05), but the serum level of albumin in the CS group was higher than that in the model group at the ninth week (P<0.05). No significant differences were observed in the serum levels of insulin and the activity of hepatic insulinase between the CS and model groups at the third week and the normal group (P>0.05). The serum levels of insulin in the CS and model groups at the sixth and ninth weeks were higher than those in the normal group (P<0.05). But the activity of hepatic insulinase was lower than that in the normal group (P<0.05 or P<0.01). No significant differences were found in the serum levels of insulin and the activity of hepatic insulinase between the CS and model groups at the third, sixth and ninth weeks (P>0.05). CONCLUSIONS: CS may decrease the damage to hepatocyte by CCl4, and inhibit hepatic fibrogenesis. Six weeks after CCl4 administration, the activity of hepatic insulinase began decreasing. CS could not inhibit the decrease of the activity of hepatic insulinase.

PMID: 14969848 [PubMed - indexed for MEDLINE]

 

Diabetes Drug Rezulin Pulled Off the Market
Medication has been linked to 63 deaths.
FDA faced strong criticism for approving treatment.

By DAVID WILLMAN, Times Staff Writer

WASHINGTON--The Food and Drug Administration said Tuesday that the popular diabetes pill Rezulin--a drug that won "fast-track" government approval but was linked to scores of liver failures and deaths--will be withdrawn promptly from the U.S. market.

Compared to alternative diabetes treatments, "continued use of Rezulin now poses an unacceptable risk to patients," said Dr. Janet Woodcock, director of the FDA's drug evaluation center.

The end for Rezulin, a Wall Street blockbuster that generated more than $1.8 billion in sales and was promoted as free of serious side effects, came Tuesday evening when Woodcock telephoned representatives of the drug's manufacturer, New Jersey-based Warner-Lambert Co. "FDA today asked the manufacturer of Rezulin . . . to remove the product from the market," the agency said in a prepared statement. "The drug's manufacturer . . . has agreed to FDA's request. "The action came 29 months after the first acknowledged death of a Rezulin patient in October 1997. The FDA has concluded that Rezulin use has "possibly or probably" resulted in 90 liver failures, including 63 deaths and seven nonfatal organ transplants.

About 300,000 Rezulin prescriptions are sold each month. "Patients taking Rezulin should consult with their physicians as soon as possible to discuss alternative therapies," Warner-Lambert said late Tuesday. "Warner-Lambert will work closely with the Food and Drug Administration . . . to assure a safe and efficient transition for patients."

Rezulin becomes the eighth prescription drug to be withdrawn from the U.S. market in the last 2 years. Among the recent withdrawals were Pondimin and Redux, ingredients in the "fen-phen" weight-reduction cocktail, found to cause heart and lung maladies, and Duract, a nonaddictive painkiller that the FDA associated with four liver-failure deaths.

More Toxic Than Two Other Drugs

The FDA noted that Rezulin is more toxic to the liver than two other similar drugs, Avandia and Actos, that also lower blood-sugar levels for adult-onset diabetics.

The drugs, approved in the last year, "offer the same benefits as Rezulin without the same risk," the FDA said. Added Woodcock: "We are now confident that patients have safer alternatives."

The FDA sought the withdrawal of Rezulin within two hours of a meeting that included agency physicians, lawyers and other specialists. According to people familiar with the private session, Dr. David J. Graham, the FDA's senior epidemiologist, said he estimated that 20 Rezulin patients a month are suffering liver failure. Graham compared Rezulin's tendency to cause fatal liver failure with the worst side effects associated with the other diabetes drugs.

He concluded that Rezulin, by far, is the most dangerous. Graham was one of at least five FDA physicians who challenged top agency officials, beginning at a staff meeting on Jan. 6, by saying that Rezulin's risks outweighed its benefits and that it should be withdrawn.

The removal of Rezulin comes after Warner-Lambert and senior FDA officials had supported its continued use in the face of mounting deaths and recent repudiation of the pill by numerous health insurers and hospitals.

On four occasions after Rezulin was made available for sale in March 1997, the FDA and Warner-Lambert agreed to safety changes in the drug's labeling, instead of pulling the pill off the market.

The FDA's stance stood in stark contrast to that of its counterpart in Britain, the Medicines Control Agency, which oversaw another company's voluntary withdrawal of Rezulin in December 1997. Citing safety concerns, the British authority refused to allow the reintroduction of Rezulin in March 1999.

But within a week, officials at the FDA, on March 26, 1999, convened an advisory committee meeting, dominated by supporters of Rezulin, including paid consultants to Warner-Lambert. At the conclusion of the meeting, Woodcock indicated in an interview that she did not share the concern voiced by Graham, the senior agency epidemiologist, who presented a chilling picture of Rezulin's danger.

Graham told the committee that Rezulin was one of the most dangerous prescription drugs on the market, that every patient taking the pill was at risk of liver failure and that there was no reliable way to safeguard them.

This flew in the face of repeated assurances from Warner-Lambert and others at the FDA, who said that patients would be adequately protected by monthly blood tests, intended to monitor their liver functions.

In June 1999, the FDA announced that it would follow the advisory committee's advice and keep Rezulin on the market. In fact, while the FDA said that Rezulin should no longer be used as a stand-alone diabetes treatment, the agency endorsed its expanded use, in "triple combination" with two other diabetes pills.

The FDA's reassessment of Rezulin's safety was in direct response to a December 1998 investigative series by The Times and subsequent articles published by the newspaper focusing on deaths related to the drug and the actions of the agency and Warner-Lambert.

The Times reported that the FDA ignored explicit signs of danger while examining Rezulin in January 1997, after a six-month review, the fastest approval granted a diabetes pill.

Complaints About Intemperate Language

The FDA approved Rezulin despite a recommendation to reject the drug by a veteran agency medical officer, Dr. John L. Gueriguian, who cited its potential danger to the liver and the heart.

Woodcock's deputy, Dr. Murray Lumpkin, stripped Gueriguian of his role in reviewing Rezulin in the fall of 1996, following complaints from Warner-Lambert about his use of intemperate language. Reached Tuesday night at his home in Rockville, Md., Gueriguian said he was pleased to hear of Rezulin's withdrawal.

"It is the right thing to do. But it is too late. Too many people have already died and suffered." Gueriguian stood alone when he opposed Rezulin in 1996. No fewer than four other FDA physicians who examined the drug endorsed its approval. They were persuaded, they said in hindsight, by Warner-Lambert's claims of safety and the pill's supposed breakthrough effectiveness.

Indeed, as recently as Feb. 24, Woodcock told reporters in a prepared statement that Rezulin "provides an effective treatment to control blood glucose and in many patients it has proven to be very effective despite the failure of other therapies."

At least three federal investigations related to Rezulin have been initiated: an inspector general's inquiry into a senior National Institutes of Health physician's acceptance of consulting fees from Warner-Lambert, an FDA inquiry into allegations that the company omitted findings of liver toxicity from a 1994 clinical trial and an FDA internal-affairs investigation into how certain agency e-mails came into the possession of The Times.

Company's Troubles Are Not Over

Having failed to hold support for Rezulin at the FDA, Warner-Lambert on Tuesday night issued this statement:

"The company has always believed that it is essential for patients and physicians to receive accurate and objective information regarding the benefits and risks of Rezulin. . . . However, repeated media reports sensationalizing the risks associated with Rezulin therapy have created an environment in which patients and physicians are simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin."

The withdrawal, however, will not end the company's troubles. Over the last year, product-liability cases have been filed in state and federal courts on behalf of patients or their survivors. One of them, Ismael "Milo" Valenzuela, whose wife, Rosa Delia Valenzuela, died in Los Angeles on Dec. 18, 1998, of liver failure after taking Rezulin, welcomed news of the withdrawal.

"That's the main thing I wanted to see, to get those pills off the market," said Valenzuela, a retired jockey who twice won the Kentucky Derby. "They killed my wife--that's the way I feel about it."

---Times researcher Janet Lundblad in Los Angeles contributed to this story

 

 

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