The new biology of diabetes

Abstract

Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion. Moreover, FOXO are necessary to maintain beta cell differentiation, and diabetes development is associated with a gradual loss of FOXO function that brings about beta cell dedifferentiation. We proposed that dedifferentiation is the main cause of beta cell failure and conversion into non-beta endocrine cells, and that treatment should restore beta cell differentiation. Our studies investigating these proposals have revealed new dimensions to the pathophysiology of diabetes that can be leveraged to design new therapies.

Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

“…The balance between the activating and repressive functions of FOXO1 is crucial in the liver since, by inducing G6pc and by inhibiting Gck , FOXO1 regulates the G6pc / Gck ratio, intracellular glucose-6-phosphate levels, and hepatic glucose handling (Haeusler et al, 2014; Pajvani and Accili, 2015). Unlike previous studies showing that insulin induction of Gck expression requires the recruitment of transcriptional activators on Gck promoter (Foretz et al, 1999; Kim et al, 2004, 2009; Roth et al, 2004), the present data show that it requires clearance of a FOXO1 corepressor.…”

“…Studies have shown beneficial effects of FOXO1 inhibition on diabetic hyperglycemia by reducing hepatic glucose production. However, these benefits can be offset by an increase in hepatic fat content (Pajvani and Accili, 2015). We have discovered small molecules with the ability to fine-tune the FOXO1 activator/repressor balance and alter the ratio of G6pc to Gck .…”

“…This is achieved through an elegant, if unexplained mechanism, whereby FOXO inhibit expression of the rate-limiting enzyme of glucose utilization, glucokinase ( Gck ) (Dong et al, 2008; Haeusler et al, 2014; Zhang et al, 2006), while stimulating the rate-limiting enzyme of glucose production, glucose-6-phosphatase ( G6pc ) (Haeusler et al, 2014; Nakae et al, 2001a). When FOXO are inhibited, glucose production decreases, potentially benefiting diabetes treatment, but hepatic lipid synthesis increases, predisposing to steatosis (Pajvani and Accili, 2015). …”

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

“…We have proposed a theory of ␤-cell dysfunction that attempts to reconcile diverse etiologies under a single mechanism and incorporates the role of insulin resistance in the process (4). We have shown that FoxO, a family of transcription factors with important roles in peripheral insulin signaling (5), also integrate various aspects of ␤-cell biology.…”

Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis

“…1 In normal physiology, fasting triggers the release of glucagon from pancreatic α-cells, which stimulates gluconeogenesis and glycogenolysis to maintain normoglycemia. 2 In the postprandial state, pancreatic β-cells dial up insulin levels to block hepatic glucose production 3–5 and utilize excess glucose for long-term energy storage in the liver in the form of glycogen, and indirectly, triglycerides.…”