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Mechanisms of insulin packaging in pancreatic beta cells: New targets in diabetes



The BAR Domain Protein Arfaptin-1 Controls Secretory Granule Biogenesis at the trans-Golgi Network.

Gehart H, Goginashvili A, Beck R, Morvan J, Erbs E, Formentini I, De Matteis MA, Schwab Y, Wieland FT, Ricci R.

Dev Cell Sept. 11, 2012

Sept. 13, 2012

Type 2 diabetes concerns 3 million people in France, i.e. 4% of the French population. The dramatic epidemics of this disease is mostly linked to a sedentary lifestyle and reduced physical activity. Romeo Ricci’s team has deciphered mechanisms as to how insulin is packaged into vesicles in pancreatic beta cells allowing insulin to be secreted. These results could be the basis of development of new anti-diabetic drugs. This study has been published online on September 13th 2012 in the journal Developmental Cell.


Insulin, a regulator of blood sugar
Insulin is a hormone secreted from beta cells in pancreatic islets and regulates glycemia (level of glucose in the blood). In these cells, synthesized insulin is packaged into vesicles at the Golgi apparatus, that subsequently detach  from this organelle to be transported to the cell surface. When arriving there, vesicles fuse with the cellular membrane releasing insulin into the blood stream.

Pancreatic beta cell dysfunction contributes to diabetes
There are two principal types of diabetes. Type 1 diabetes results from the destruction of pancreatic cells leading to a severe reduction or loss of insulin in the blood. 80% of diabetes concerns type 2 diabetes, a complex disease frequently associated with other clinical traits including obesity or cardiovascular disorders. Metabolic overloading combined with an increase of body fat enhances insulin demands in the body. In a first step, pancreatic beta cells are able to boost their insulin production but, in long term, cellular stress occurs resulting in reduced insulin secretion and development of overt diabetes.
Focus on mechanisms of secretory vesicle biogenesis
While most attention in this field has been drawn to granule fusion with the plasma membrane, mechanisms of vesicle formation at the Golgi apparatus are not well known thus far. Helmuth Gehart et al. in the laboratory of Romeo Ricci have worked on mechanisms of insulin vesicle generation. They discovered that the protein Arfaptin-1 is crucial in the control of granule formation. They have demonstrated that Arfaptin-1 prevents vesicle detachment from the Golgi apparatus. This crescent-shaped protein wraps the neck of a budding vesicle, protecting it from detachment from the Golgi apparatus. Once a proper vesicle size and correct loading with protein is achieved, Arfaptin-1 is phosphorylated and cut through the vesicle neck, allowing its detachment from the Golgi apparatus. In this study, researchers have demonstrated that interference with this pathway causes strong disturbance in insulin secretion, which is also frequently seen in patients suffering from type 2 diabetes.
One option in type 2 diabetes treatment is to enhance insulin secretion. However, none of the currently available drugs target insulin granule formation at the Golgi. These recent results are opening new perspectives to develop therapies in this direction. Importantly, this mechanism may not be restricted to insulin secretion but might be important in other secretory cells opening potentially wider therapeutic options.

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