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.

Keywords: Beta cell failure; Bile acid; Cholesterol; Dedifferentiation; Diabetes outcome; FOXO; Heart disease; Hepatic glucose production; Lipoprotein; Notch 1; Review.

Fig. 1

Integrative physiology of FOXO proteins. FOXO proteins participate in multiple physiological processes that affect not only metabolism, but also the immune system and cell proliferation in oncogenesis. Key metabolic functions reviewed in this article are summarised here

Fig. 2

Dual role of hepatic FOXO in determining intracellular G6P levels. Glucose-6-phosphate (G6P) levels are the result of opposing actions of G6PC and glucokinase. FOXO protein exert control over both, but likely by different modes of action. FOXO directly increase G6PC expression, while inhibition of the GCK gene encoding glucokinase is likely to be indirect through a currently unknown effector corepressor

Fig. 3

Role of hepatic insulin resistance in diabetes. Excessive hepatic glucose production causes hyperglycaemia, and contributes to microvascular complications. An atherogenic lipoprotein profile can also be caused in the liver through increased secretion of VLDL-TG and decreased clearance of LDL-cholesterol. These processes are also tightly linked to cellular actions of insulin. For example, insulin can control triacylglycerol synthesis through SREBP1c, cholesterol synthesis through SREBP2, lipoprotein processing and secretion, and cholesterol clearance through its combined actions on LDL receptors and proprotein convertase subtilisin/kexin type 9 (PCSK9)

Fig. 4

Regulation of CYP8B1 by FOXO. In addition to their effects on glucose and lipid synthesis, FOXO can affect peripheral metabolism by regulating the composition of the bile acid pool. CYP8B1 encodes the 12α-hydroxylase activity that converts chenodeoxycholic and lithocholic acid into cholic and dexoycholic acid. By virtue of their differential affinities for the primary bile acid receptor, FXR, these bile acids can have differential effects on lipid synthesis, cholesterol turnover and glucose levels. 12-OH BA, 12α-hydroxylated bile acids; VLDL-TG, VLDL-triacylglycerol

Fig. 5

Fate of FOXO in cells during diabetes development. Immunohistochemistry with FOXO1 (green) and insulin (red) in mouse pancreatic islets. In healthy islets, FOXO1 colocalises with insulin to the cell’s cytoplasm, indicating that it is inactive. During the early phases of diabetes, FOXO1 translocates to the nucleus in a characteristic punctate pattern, indicating that it is being activated. Over time, this response is lost, and FOXO1 disappears. This, in turn, brings about a gradual loss of insulin content

Fig. 6

A model of metabolic inflexibility in beta cells. (a) The healthy beta cell secretes insulin in a bi- (or tri-) phasic fashion. The first phase is dependent on glucokinase-dependent glucose phosphorylation; the second phase is dependent on various mitochondrial signals, as indicated, which in turn arise from either glucose-, lipid- or amino acid-derived acyl-CoA. We have proposed that FOXO preserve the balance of mitochondrial function by supporting the MODY gene networks and suppressing the PPARα-dependent lipid oxidising pathway. (b) When FOXO become functionally exhausted, this balance breaks down, and mitochondria are flooded with an oversupply of lipid-derived acyl-CoA, which promotes peroxide formation and other biochemical abnormalities that impair insulin secretion, eventually leading to dedifferentiation. CaV, voltage-dependent Ca²⁺ channel; CPT1, carnitine palmitoyltransferase 1; GDH, glutamate dehydrogenase; HNF, hepatocyte nuclear factor; K_ATP, ATP-sensitive potassium channel; Lc-FA, long-chain fatty acids; PC, pyruvate carboxylase; PDX1, pancreatic and duodenal homeobox 1

Fig. 6

A model of metabolic inflexibility in beta cells. (a) The healthy beta cell secretes insulin in a bi- (or tri-) phasic fashion. The first phase is dependent on glucokinase-dependent glucose phosphorylation; the second phase is dependent on various mitochondrial signals, as indicated, which in turn arise from either glucose-, lipid- or amino acid-derived acyl-CoA. We have proposed that FOXO preserve the balance of mitochondrial function by supporting the MODY gene networks and suppressing the PPARα-dependent lipid oxidising pathway. (b) When FOXO become functionally exhausted, this balance breaks down, and mitochondria are flooded with an oversupply of lipid-derived acyl-CoA, which promotes peroxide formation and other biochemical abnormalities that impair insulin secretion, eventually leading to dedifferentiation. CaV, voltage-dependent Ca²⁺ channel; CPT1, carnitine palmitoyltransferase 1; GDH, glutamate dehydrogenase; HNF, hepatocyte nuclear factor; K_ATP, ATP-sensitive potassium channel; Lc-FA, long-chain fatty acids; PC, pyruvate carboxylase; PDX1, pancreatic and duodenal homeobox 1