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Endocrine Discovery |
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 Top Endocrine Discovery Endocrine PracticeMilestones in EndocrinologyIn the Journal 25... |
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Insulin- and oral hypoglycemic agent-treated type 2 diabetic patients receiving pramlintide were more likely to achieve HbA1C < 7% with less weight gain and fewer hypoglycemic events, but more nausea, in a 24-week randomized open-label study of 113 patients with type 2 diabetes assigned to receive either mealtime pramlintide (120 µg) or a titrated rapid acting insulin. (Diabetes Care [September 2009] 32(9):1577)
HbA1C underestimated mean glucose by 29 mg/dl, whereas fructosamine more closely reflected glycemia in a cross sectional study of 100 HIV-infected adults with type 2 diabetes or fasting hyperglycemia. (Diabetes Care [September 2009] 32(9):1591)
Vertebroplasty achieved no difference in overall pain scores or other outcome measures than a sham procedure at 1 week or at 1, 3, or 6 months in a randomized, double-blind, placebo-controlled trial of 78 patients with one or two painful osteoporotic vertebral fractures. (N Engl J Med [August 6, 2009] 361(6):557)
Between 1985 to 2005, a 32% decrease in age-specific hip fracture rates in women and a 25% decrease in men was observed in a Canadian study of nationwide hospitalizations for hip fractures, with greater decreases seen in fractures since 1996. (JAMA [August 26, 2009] 302(8):883)
A new genetic variant associated with type 2 diabetes, insulin resistance, and hyperinsulinemia was discovered. The SNP, located adjacent to the insulin-receptor substrate 1 gene (IRS1), was discovered using genomewide association data from more than 14,000 French, Danish and Finnish participants from population-based cohorts. (Nat Genet [published ahead of print September 6, 2009])
Venous thrombosis risk in combined oral contraceptives users was found to decrease with duration of use and decreasing estrogen dose. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis. (BMJ [September 5, 2009] 339(7720):b2890)
Pioglitazone is associated with a significantly lower risk of heart failure and death than rosiglitazone in a retrospective cohort study of outpatients aged 66 years and older who were started on the two formulations. (BMJ [September 5, 2009] 339(7720):b2942)
An association between human exposure to DDE and incident diabetes was demonstrated in a cohort of Great Lakes sport fish consumers. (Environ Health Perspect [July 2009] 117(7):1076)
Endoplasmic reticulum stress signals were found to induce hepcidin expression and cause hypoferremia and spleen iron sequestration in mice, indicating a role for CREBH in ER stress–regulated hepcidin expression. (Science [August 14, 2009] 325(5942):877)
Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma. (Science [August 28, 2009] 325(5944):1139)
PRDM16 works together with C/EBP-β and expression of this transcriptional unit induces a fully functional brown fat program in naive fibroblasts. Transplantation of such fibroblasts into mice creates a brown fat pad that acts as a sink for glucose. (Nature [August 27, 2009] 460(7259):1154)
Interferon regulatory factor-8 (IRF-8) has been indentified as an inhibitor of osteoclast formation. (Nat Med [September 2009] 15(9):1066)
p53 expression in adipose tissue is central to the development of insulin resistance, and suggests that cellular aging signals in adipose tissue, and could represent a new target for diabetes treatment. (Nat Med [September 2009] 15(9):1082)
Denosumab is Promising New Osteoporosis Drug
Denosumab has been used successfully to reduce bone resorption and increase bone mineral density (BMD). Now, a new international randomized study has shown its effectiveness in preventing fracture in postmenopausal women with osteoporosis as well.
Led by Steven R. Cummings, M.D., the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) team of researchers randomly assigned 7,868 women ages 60–90 to two groups, one receiving 60 mg of denosumab subcutaneously twice yearly for 3 years, the other, placebo. Both groups also took 1,000 mg calcium supplements. Eligible subjects had a BMD T score between –2.5 and –4.0 at the lumbar spine or total hip, had no existing severe fractures, and had not taken bisphosphonates or strontium for osteoporosis.
Denosumab reduced the risk of vertebral fracture by 68%—the cumulative incidence, based on Kaplan-Meier estimates, of vertebral fracture in the denosumab group was 2.3%, compared to 7.2% among the placebo group. Hip and nonvertebral fracture were secondary study endpoints and, likewise, showed significant risk decreases (40% and 20%, respectively).
Dolores Shoback, M.D., Professor of Medicine at the University of California, San Francisco, in the Endocrine Research Unit at the San Francisco VA Medical Center says the fracture reduction study was well-designed. "The results are exciting," she says, "because the drug shows across-the-board efficacy against the major osteoporotic fractures, and has an acceptable adverse-event profile."
Denosumab is a fully human monoclonal antibody that binds receptor activator for nuclear factor-
B ligand (RANKL), a cytokine that fosters osteoclast-mediated bone resorption, and prevents its interaction with its receptor, RANK. Whereas bisphosphonates block osteoclast action only, denosumab also prevents their formation. This is a new drug target, says Dr. Shoback, the first in its class. Denosumab reduced bone resorption an average of 86% in 1 month—a reduction greater than that of other antiresorptive drugs—possibly because of its novel mechanism of action.
Denosumab also proved highly effective at increasing BMD. The increase was 9.2% at the lumbar spine and 6% at the total hip.
Because RANKL is a member of the tumor necrosis factor superfamily and involved in immunity mediation, there has been concern that its inhibition would increase cancer and infection risks. To date, a minor increase in cases of cellulitis needing hospitalization was seen in denosumab-treated versus placebo-treated patients in the FREEDOM study.
Its effectiveness in preventing fracture risk and increasing BMD recommend denosumab as an alternate therapy for osteoporosis, but it is so far not FDA-approved. More long-term studies are needed to confirm its lack of adverse effects.
A potential advantage of denosumab is its administration. Patients receive twice yearly subcutaneous injections, rather than taking daily or weekly tablets. "This novel administration schedule could improve adherence. A big problem with osteoporosis therapies is getting patients to stay on them consistently," says Dr. Shoback. (N Engl J Med [August 20, 2009] 361(8):756)
Mediterranean Diet Delays Need for Drug Therapy in Type 2 Diabetes
According to the American Diabetes Association, patients with type 2 diabetes (T2D) require both lifestyle changes and drug therapy because neither method alone is sufficient to keep their disease in check. With 380 million cases projected by 2025, the pandemic of T2D has led researchers to explore ways to improve existing treatment methods. Lifestyle changes currently recommended include losing weight on a low-fat, low-carbohydrate diet. A new study suggests that following a Mediterranean-style diet of fewer carbohydrates is more effective than reducing fat, providing longer-term benefits.
Led by Katherine Esposito, M.D., Ph.D., the Italian research team followed 215 overweight, sedentary people newly-diagnosed with T2D with no prior diabetes drug treatment, for 4 years. Half of the subjects were put on a diet rich in whole grains, based on American Heart Association guidelines restricting fat to less than 30% of overall intake.
The remaining subjects followed a Mediterranean-style diet of vegetables, nuts, poultry, and fish. No more than 50% of calories came from complex carbohydrates, and no less than 30% from monounsaturated fat, derived primarily from olive oil.
All subjects were counseled bimonthly for the duration of the study to eat a healthy diet and to exercise. Women consumed about 1,500 kcal/d, and men, about 1,800 kcal/d. They kept food diaries for researchers to monitor diet adherence.
The primary endpoint of the study was delaying the need for antihyperglycemic pharmacotherapy. Secondary endpoints included reducing body mass index (BMI) and waist circumference, controlling glucose levels, and reducing risk for coronary disease. After 1 year, subjects on the Mediterranean diet lost an average of 4.4 lbs more weight and showed a 1.0 kg/m2 greater reduction in BMI and 1.3 cm in waist circumference. These differences leveled off in the last 3 trial years.
The need for medication, however, remained significantly lower among the Mediterranean-diet group throughout the trial. After 18 months, 24% of participants in the low-fat group required pharmacotherapy compared to only 12% in the Mediterranean-diet group. By study’s end, that difference was 70% and 44%, respectively.
The Mediterranean-style diet, therefore, conferred benefits that surpassed weight loss. Researchers suggest that monounsaturated fats improved insulin sensitivity possibly through increased circulating adiponectin levels, which delayed the need for antihyperglycemic medication.
Steven Kahn, Professor of Medicine in the Division of Metabolism, Endocrinology and Nutrition at the VA Puget Sound Health Care System and University of Washington says, "The findings are of interest as they are in keeping with the Diabetes Prevention Program and the Finnish Diabetes Prevention Study, both of which demonstrated that a lifestyle intervention and weight loss with involved dietary changes reduced progression of impaired glucose metabolism to diabetes."
Implications for T2 diabetics are encouraging. Pharmacotherapy for T2D has been shown to become less effective over time and can have associated cardiovascular risks. Delaying the need for antihypertensive medication and improving lifestyle, therefore, could help those with T2D manage the disease better and longer.
"The importance of lifestyle intervention across the spectrum of elevated glucose disorders is becoming more and more apparent," says Dr. Kahn. "The future challenge for practitioners is to successfully implement these changes in our community," he says. (Ann Intern Med [September 1, 2009]151(5):306)
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Endocrine Practice |
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TopEndocrine DiscoveryEndocrine PracticeMilestones in EndocrinologyIn the Journal 25... |
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Generex Biotechnology Corporation received approval for its oral insulin spray, Oral-lyn. (For more information, go to: http://investor.generex.com/releasedetail.cfm?ReleaseID=408392)
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Milestones in Endocrinology |
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TopEndocrine DiscoveryEndocrine PracticeMilestones in EndocrinologyIn the Journal 25... |
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In the Journal 25 Years Ago |
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TopEndocrine DiscoveryEndocrine PracticeMilestones in EndocrinologyIn the Journal 25... |
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"Three patients with hypercalcemia associated with malignant lymphoma and elevations in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] are described. ...These findings confirm an earlier observation that elevated plasma levels of 1,25-(OH)2D may occur in certain patients with lymphoma and suggest that this vitamin D metabolite may act as a humoral or systemic mediator of hypercalcemia. Proof that this is the case and identification of the source of 1,25-(OH)2D production will require further study."
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