4 New Diabetes Links

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Diabetes mellitus (DM) has strong associations with many other conditions. The reports that follow show recently identified links with heart failure, insulin resistance, cancer, and nonalcoholic fatty liver disease (NAFLD).

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Incretin-based Drugs May Not Increase Heart Failure Risk

Raison d’etre: Antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, may increase the risk of heart failure.

Results: In a multicenter, observation study of close to 1.5 million patients (nearly 30,000 were hospitalized for heart failure), the rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic drug combinations. Results were similar for DPP-4 inhibitors and GLP-1 analogues.

Bottom line: In this analysis from large cohorts of patients with DM, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure.

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Cancer Drug May Aid Insulin Resistance and Diabetes

Raison d’etre: The tyrosine kinase inhibitor imatinib (Gleevec), which has revolutionized treatment of chronic myeloid leukemia, also blocks phosphorylation of peroxisome proliferator–activated receptor (PPAR)γ at Ser²⁷³, one of the key mechanisms for antidiabetes drugs to target PPARγ.

Results: In high fat–fed mice, Gleevec improved insulin sensitivity without causing severe adverse effects associated with other PPARγ-targeting drugs. Gleevec also reduced lipogenic and gluconeogenic gene expression in the liver and ameliorated inflammation in adipose tissues.

Clinical implications: Gleevec appears to exhibit beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPARγ phosphorylation.

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Proteins Link Obesity and Diabetes with Cancer

Raison d’etre: Diseases of chronic inflammation or disordered metabolism, such as type 2 DM, may be related to cancer through shared mechanisms that regulate chromatin.

Results: Reducing levels in pancreatic beta cells of individual Bromodomain and Extra-Terminal (BET) proteins, previously shown to play a role in cancer, also may help patients who are obese and have DM.

Clinical implications: BET proteins provide a new pathway to connect adult-onset DM with cancer, so properly targeting BET proteins may be helpful for both diseases.

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Gestational Diabetes Strongly Associated With NAFLD

Raison d’etre: Insulin resistance is central to the development of NAFLD, and gestational DM is an early marker of insulin resistance.

Results: In a multicenter community-based longitudinal cohort study of 1115 women who underwent CT quantification of hepatic steatosis 25 years after entry, 11% reported a history of gestational DM and 7% met the CT definition for NAFLD at year 25. The crude risk of NAFLD at 25 years was more than 2.5-fold greater in women who had gestational DM than in women who did not.

Clinical implications: Gestational DM is a risk marker for NAFLD and represents an opportunity to identify women at risk for NAFLD at a young age.

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Summary:

• DPP-4 inhibitors and GLP-1 analogues do not appear to increase the risk of heart failure.

• The cancer drug Gleevec shows promise as a novel therapeutic agent for use in insulin resistance and type 2 DM.

• Newly discovered proteins may be linked to obesity-driven DM and to cancer.

• A history of gestational DM may help identify young women at risk and allow targeted strategies to prevent complications related to NAFLD.

Disclosures:

1. Filion KB, Azoulay L, Platt RW, et al. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374:1145-1154.

2. Choi SS, Kim ES, Jung JE, et al. PPARγ antagonist Gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes. 2016;65:829-839.

3. Deeney JT, et al. BET Bromodomain proteins Brd2, Brd3 and Brd4 selectively regulate metabolic pathways in the pancreatic β-cell. PLoS One. 2016;11(3):e0151329. doi: 10.1371/journal.pone.0151329. eCollection 2016.

4. Ajmera VH, Gunderson EP, VanWagner LB, et al. Gestational diabetes mellitus Is strongly associated with non-alcoholic fatty liver disease. Am J Gastroenterol.2016 Mar 22. doi: 10.1038/ajg.2016.57. [Epub ahead of print]