Type 2 Diabetes it is a global problem that is continuously, inexorably and constantly increasing. In fact, it is estimated that from 1980 to 2008 the number of new diagnoses of diabetes (for 90% type 2) increased from about 153 to 347 million worldwide. Often it is a silent condition, which has a significant clinical and economic impact and is capable of influencing patients' lives in an important way.


During this particular year, then, Type 2 Diabetes has received special attention, as several studies demonstrated an association between the presence of type 2 diabetes and a poor prognosis following SARS-COV2 infection, due to an uncontrolled cascade of inflammatory mediators.

There have been several Italian researchers who, over the years, have dealt with what appears to be a disabling condition in all respects. Our compatriots around the world have distinguished themselves for their dedication to work and to one Research career which often led them to lose sleep, to spend their best years away from their land, in the name of an ideal that had only one goal: help people affected by this disease and related comorbidities.

Among these, hypercholesterolemia plays a very important role.

An interesting study, carried out in the big apple, evaluated the role of glucagon and its hepatic receptor, in the metabolic response to fasting, in terms of blood sugar and cholesterol. 

What is glucagon?

Glucagon is the major regulator of glucose production in the liver, through a system of G protein-coupled receptors and the activation of adenylate cyclase.

PCSK9 protein and hepatic glucagon receptor

Its hepatic receptor, in particular, is involved in the regulation of cholesterol homeostasis, in particular LDL, through the regulation of a recently identified protein, proprotein convertase subtilisin / kexin type 9 (PCSK9). This protein binds to the LDL receptor on the cell surface, which is internalized. This internalization involves a lack of binding of the LDL, which therefore remain in circulation. 

The regulation of PCSK9 by glucagon occurs through the Epac2 / Rap1 pathway (exchange protein directly activated by cAMP-2 / Ras-related protein-1). Training, which involved gene silencing techniques in the animal model, demonstrated how the activation of the glucagon receptor signal was able to regulate the PCSK9 protein (and therefore the circulating LDL levels) but without modifying its expression. 

Author of these promising results is Stefano Spolitu, from Cagliari but with New York in the heart, who will soon be a guest of our column and will tell us the background of this beautiful discovery. 

Stay tuned!


  • Hartstra AV, Bouter KE, Bäckhed F, Nieuwdorp M. Insights into the role of the microbiome in obesity and type 2 diabetes. Diabetes Care. 2015; 38 (1): 159-165. doi: 10.2337 / dc14-0769
  • Yehya A, Carbone S. Managing type 2 diabetes mellitus during COVID-19 pandemic: The bittersweet. Diabetes Metab Res Rev. 2021; 37 (1): e3360. doi: 10.1002 / dmrr.3360
  • Spolitu S, Okamoto H, Dai W, et al. Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol. Circ Res. 2019; 124 (1): 38-51. doi: 10.1161 / CIRCRESAHA.118.313648


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