Glucagon is currently used as an emergency treatment of severe diabetic hypoglycemia, which is associated with low blood glucose levels.

Glucagon is an important protein for the control of blood sugar levels. Normally, glucagon stimulates a temporary increase in blood sugar levels and then a decrease to normal levels. However, in diabetes and obesity, this response is impaired and blood sugar levels do not decrease. TGRI Senior Scientist Dr. Tony Lam has discovered that glucagon regulates the increase and subsequent decrease in blood sugar through actions in the hypothalamus, the region of the brain responsible for regulating sugar production by the liver. A signalling mechanism in the hypothalamus, known as the protein kinase A (PKA) pathway, was responsible for mediating glucagon's control over blood sugar levels.

Dr. Lam's group examined experimental models of diabetes and obesity and observed that the hypothalamus improperly responded to glucagon by only increasing blood sugar, a characteristic of these conditions. However, when the PKA pathway was directly activated, blood sugar levels decreased to normal, suggesting that the hypothalamus develops a resistance to glucagon in diabetes and obesity. "These findings also indicate that drugs that target glucagon action in the brain could regulate sugar levels in diabetes," says Dr. Lam.

This work was supported by the Canadian Diabetes Association. Dr. Lam holds the John Kitson McIvor Endowed Chair in Diabetes Research and is a Tier 2 Canada Research Chair in Obesity.

Hypothalamic glucagon signaling inhibits hepatic glucose production. Mighiu PI, Yue JT, Filippi BM, Abraham MA, Chari M, Lam CK, Yang CS, Christian NR, Charron MJ, Lam TK. Nature Medicine. 2013 May 19. [Pubmed abstract]

KRAS mutations are usually found in the non-small-cell lung cancers of smokers.

The KRAS gene, which encodes a signalling protein in mammalian cells, is often mutated in patients with non-small-cell lung cancer (NSCLC). Previous studies suggest that KRAS mutations are predictive of poorer outcomes in these patients; however, these investigations have shown significant variation that has left the prognostic and predictive value of these mutations unclear.

A recent study from the LACE-Bio Collaborative Group, led by OCI Clinician Scientist Dr. Frances Shepherd and OCI Senior Scientist and pathologist Dr. Ming-Sound Tsao, examined the impact of KRAS mutations on survival benefit from adjuvant chemotherapy for lung cancer patients. Based on data collected from four clinical trials, they showed that KRAS mutation status is not significantly prognostic and does not predict a differential benefit from patients who received adjuvant chemotherapy. However, patients with KRAS mutations in their primary tumours had an increased risk of developing second primary cancers in the observation arms of the trials. Dr. Shepherd explains, "Although our results demonstrate that KRAS mutation status cannot be used to select patients with NSCLC for adjuvant chemotherapy, we did observe interesting differences in overall survival after adjuvant chemotherapy associated with KRAS mutation subtypes, particularly those with codon 13 mutations. This clearly warrants further study."

This work was supported by la Ligue Nationale Contre le Cancer, le Programme National d’Excellence Spécialisé cancer du poumon de l’Institut du Cancer, the National Cancer Institute, the Canadian Cancer Society Research Institute, Sanofi and The Princess Margaret Cancer Foundation.

Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. Shepherd FA, Domerg C, Hainaut P, Jänne PA, Pignon JP, Graziano S, Douillard JY, Brambilla E, Le Chevalier T, Seymour L, Bourredjem A, Le Teuff G, Pirker R, Filipits M, Rosell R, Kratzke R, Bandarchi B, Ma X, Capelletti M, Soria JC, Tsao MS. Journal of Clinical Oncology. April 29 2013. [Pubmed abstract]

Having more joint damage scored on radiographs before treatment was associated with damage progression.

Psoriatic arthritis (PsA) is a progressive type of arthritis that develops in people with psoriasis, a chronic skin condition. The pain and swelling of the joints can progress to bone erosion, narrowing of the space between bones in a joint and even total joint destruction, damage that can be seen on an X-ray. Methotrexate is a widely used therapy for PsA, though there is limited evidence for its efficacy. Drugs that inhibit tumour necrosis factor alpha (TNFα) have been found to reduce the progression of joint damage, supported by findings that TNFα is elevated in the joints of patients with PsA. TWRI Senior Scientist Dr. Dafna Gladman conducted a study to determine which therapy was more effective at preventing the accumulation of joint damage in patients with PsA.

The investigation found that TNFα blockers provided an even larger benefit to patients with PsA than methotrexate. 88% of the patients receiving the conventional methotrexate therapy had increased joint damage as measured by radiography four years after starting treatment, versus 61% of patients on the TNFα blockers. "Our study supports the superiority of TNFα blockers over methotrexate to prevent joint damage," concludes Dr. Gladman.

This work was supported by the Arthritis Society, the Canadian Institutes of Health Research and the Krembil Foundation.

Tumour necrosis factor α blockers are more effective than methotrexate in the inhibition of radiographic joint damage progression among patients with psoriatic arthritis. Eder L, Thavaneswaran A, Chandran V, Gladman DD. Annals of the Rheumatic Diseases. 2013 April 25. [Pubmed abstract]