Joslin Diabetes Research - Section Details

Mechanisms of Insulin Action

The laboratories in the CMP section aim to elucidate pathophysiological mechanisms in insulin resistance, b-cell function and the development of type 2 diabetes, and to exploit this knowledge to create new and better treatments. While we have not yet changed the name of the section, for example to integrative physiology or systems biology, this would be a natural progression since past strengths in biochemistry and cell biology have increasingly given way to new and additional strengths in animal and human physiology and pathology, immunology, genetics, genomics and pharmacology. Dating back to its leadership under Ron Kahn, the CMP section has had strengths in the areas of insulin action and inaction (i.e. insulin resistance). However, we have increasingly realized that insulin resistance and diabetes cannot be approximated using in vitro culture models, but must be studied in vivo. This is because multiple tissues and organs participate both in normal metabolic
regulation as well as pathological dysregulation in obesity and type 2 diabetes. Integrative approaches are used in animal studies and the translational bench-to-bedside studies with human subjects. In addition to human genomic and pharmacogenomic profiling studies underway, the section has also undertaken new initiatives in clinical research, which may translate into new treatments for patients with diabetes.

Shoelson lab:

This lab’s primary focus is on obesity-induced inflammation in promoting insulin resistance, type 2 diabetes and cardiovascular disease; it also studies the roles of inflammation in related chronic conditions including NASH and diabetic nephropathy and the progression of these disorders. Studies range from basic biochemistry and structural biology to signal transduction, immunology and cell biology to animal and human physiology and clinical trials, as bulleted below:

Tissue-specific effects of inflammation in the pathogenesis of insulin resistance.

Characterization of the immune cells in fat and liver in obesity-induced inflammation.

Genetic mediators and acquired alterations in inflammation in insulin resistance and type 2 diabetes.

Relationships between obesity-induced inflammation and increased risk for atherosclerosis.

Serine/threonine phosphorylation of insulin receptors and substrates in insulin resistance.

Structural biology of insulin signaling and insulin resistance.

TINSAL: Clinical trials to Target INflammation using SALsalate in type 2 diabetes, cardiovascular disease impaired glucose tolerance and diabetic nephropathy.

Patti lab:

The lab focuses on understanding transcriptional mechanisms mediating the effects of genetic and environmental risk for insulin resistance and type 2 diabetes. The majority of studies are translational, utilizing tissue samples from metabolically characterized human subjects to evaluate gene-expression patterns related to diabetes risk. Current projects include:

Mechanisms mediating obesity-related impairments in mitochondrial gene expression and function

Identification of patterns of dysregulation of gene expression in humans with insulin resistance and prediabetes linked to family history of diabetes and low birth weight

Prenatal and perinatal nutritional factors linked to obesity and diabetes risk

Kulkarni lab:

This lab strives to understand the role of growth factor signaling in islet cells. Investigations attempt to determine the mechanisms that underlie α- and β-cell regeneration, with a long-term goal of replacement therapy. To this end, the lab has created mouse models lacking growth factor signaling proteins in α- and β-cells and derived cell lines from the mutant mice to study details of molecular signaling. Studies extend to autopsied pancreas and freshly isolated islet tissues from patients with type 2 diabetes. In the area of type 1 diabetes, the lab focuses on how insulin/IGF-I signaling impacts the α-cell’s ability to counter hypoglycemia – an important problem for patients treated with insulin. Finally, the lab recently began to examine signaling cross-talk between growth factors and leptin in islet cells to explore relationships in the context of obesity.

Five recent “highpoints”:

Discovered new roles for the transcription factor NF-kB in the pathogenesis of obesity-induced insulin resistance and showed that inhibiting this pathway holds promise in the treatment and prevention of obesity-related conditions, including insulin resistance, type 2 diabetes and cardiovascular disease. Major clinical trials are underway. Science, 2001; Nat. Med., 2005; J Clin. Invest. (2006).

Discovered links between insulin resistance/diabetes and the impaired expression of PGC1 and a constellation of nucleus-encoded mitochondrial genes. PNAS, 2003.

Showed that tissue-specific deficiencies in insulin and IGF-1 receptors lead to β-cell secretory dysfunction while not altering β-cell development. Nat. Gen., 2006.

Discovered a new role for NF-kB in cachexia and other syndromes of skeletal muscle wasting. Cell, 2004.

Showed that the physiological and imprinted effects of maternal/fetal malnutrition are partially reversible through early postnatal nutritional repletion. Diabetes, 2005.