III- Factors underlying beta-cell dysfunction in type 2 diabetes

Jean Christophe Jonas (Brussels, Belgium) reviewed the stresses that high glucose concentration imposes on pancreatic islets. Under hyperglycaemic conditions, alterations are seen in beta-cell gene expression, function, survival and growth. These changes result from a range of stresses on the beta-cell including oxidative stress, endoplasmic reticulum stress, cytokine-induced apoptosis and hypoxia. Interestingly, recent animal studies have demonstrated that oxidative stress on beta-cells is greatest at low and high glucose concentrations compared with intermediate concentrations. Further understanding of the various cellular stress-response pathways will enable the development of new complementary therapeutic strategies that reduce beta-cell stress and improve beta-cell survival in diabetic patients.

Vincent Poitout (Montreal, Canada) highlighted the importance of cell-membrane receptors coupled to the G protein (GPCRs), specifying that these represent potential targets of a number of therapeutic strategies. In recent years, it has been demonstrated that several GPCRs on beta-cells are activated in the presence of lipids. Among these, the free fatty acid receptor 1 (GPR40) is implicated in the amplification of secretion of insulin induced by glucose.
Possible future therapeutic strategies in diabetes could therefore comprise pharmacological activation of GPR40.
Other GPCRs, expressed in beta cells and/or intestinal L cells, include the G protein–coupled receptors 119 (GPR119) and 120 (GPR120). Both of these receptors increase circulating insulin levels through a direct insulinotropic action
on beta cells, and through mediating fatty acid stimulation of incretin secretion. Clearly, the recent identification of
these cell-membrane receptors has opened up exciting new avenues for drug development concerning the management of type 2 diabetes.

Domenico ACCILI (New York, USA) discussed how the beta-cell becomes defective during insulin resistance, leading to development of a diabetic state. The earliest reaction to peripheral insulin resistance is an increase in insulin production and secretion. The resulting hyperinsulinemia promotes an increase in beta-cell mass mostly due to an increase in beta-cell replication. However, animal and human models demonstrated that, after the onset of diabetes, there is a gradual deterioration in beta-cell function and mass. The Forkhead Transcription Factor (Fox01) represents a key regulatory protein in these processes (Figure 3). Fox01 is part of a family of transcription factors that control the
expression of genes involved in fundamental cellular processes such as apoptosis, responses to oxidative stress, cellular proliferation, cellular differentiation, and regulation of energy metabolism. When considering therapeutic interventions for the management of type 2 diabetes, the main question for the clinician is whether beta-cell function
should be preserved by decreasing its metabolic demand, or should beta-cell function be increased to overcome insulin resistance. Ideally, however, preservation of beta-cell function is preferable rather than treating dysfunction once it is already established.

Figure 3. The effects of the Fox01 transcription factor in the type 2 diabetic patient

FOCUS: oxidative and endoplasmic reticulum stress

1. Oxidative stress

High glucose concentrations generate oxidative stress through an increase in the production of reactive oxygen species (ROS) in a variety of cell types, including beta cells. When intracellular glucose concentrations exceed the glycolytic capacity of the beta cell, excess glucose is shunted to enolization pathways, resulting in superoxide (O2
-) production. Oxidative stress increases the rate of chromosomal telomere shortening by stimulating strand breaks in telomeric DNA. Subsequent shortening of telomeres to a “critical length” triggers cells to undergo replicative senescence and apoptosis.
Beta cells express low levels of antioxidant enzymes, and are therefore highly sensitive to oxidative stress. Various in vitro strategies that increase beta-cell antioxidant defences have been shown to reduce oxidative stress occurring in culture under both low and high glucose concentrations. However, conclusive evidence that antioxidants improve beta-cell function and survival in patients with type 2 diabetes is still lacking (Jonas lecture).

2. Endoplasmic reticulum stress

Proper folding, maturation, storage and transport of proteins take place in the endoplasmic reticulum (ER). Accumulation of unfolded proteins, and extreme energy and nutrient fluctuations (glucolipotoxicity, hypoxia, etc.) cause disturbances in the ER lumen and create beta-cell stress. This activates a complex signalling network, the unfolded protein response (UPR), which aims to restore normal ER function through attenuation of translation, degradation of misfolded proteins, and augmented transcription of ER chaperones to increase protein folding capacity. If the UPR fails to restore adequate ER function, it initiates cellular apoptosis.5
ER stress is a feature of beta-cell glucolipotoxicity and may also initiate the development of insulin resistance and inflammation of adipose tissue in obesity and type 2 diabetes. There are two principal inflammatory pathways activated by cytokines (such as TNF-α) and fatty acids that lead to disruption of insulin action. These are the JNK/AP-1 (c-JUN NH2-terminal kinase-activator protein-1) pathway and the IKK–NF-κB (inhibitor κB kinase–nuclear factor κB) pathway. Both of these pathways are associated with molecules involved in UPR signalling. Moreover, the ER itself is a major source of ROS and oxidative stress emanating from the ER can also activate both JNK/AP-1 and IKK–NF-κB and potentially give rise to insulin resistance (Jonas lecture).


Fatty acids (FAs) acutely amplify glucose-stimulated insulin secretion (GSIS) rather than directly initiating insulin release. In contrast, prolonged exposure to elevated levels of FAs impairs beta-cell survival and insulin secretion. The stimulatory and inhibitory effects of FAs on insulin secretion appear to require intracellular metabolism of FAs and the generation of lipid-derived metabolites. There is also evidence that FAs induce a variety of physiological responses
by activating GPR40. GPR40 (or free fatty acid 1 receptor [FFA1R]) is highly expressed in pancreatic beta-cells and insulin-secreting cell lines and is activated by medium to long-chain FAs.6 Inactivation of GPR40 using small interfering RNA or pharmacological agents suppresses FA upregulation of GSIS in vitro. Furthermore, deletion of GPR40 in transgenic mice results in impaired, but not abolished, insulin secretory responses to intravenous glucose
and lipids.6 This implies that both processes, namely GPR40-mediated signalling and intracellular metabolism of FAs, are implicated in FA-upregulation of GSIS. GPR40 would thus be involved at least in 50% of the FA effect on beta-cell insulin secretion during short-term glucose stimulation but uninvolved in the longer-term FA inhibition of beta-cell function. This is consistent with the considerable evidence implying that intracellular FA metabolism underlies the inhibitory effects of FAs on beta-cell function.

Interestingly, GPR40 mediates FA-stimulated insulin secretion from the beta-cell not only directly but also indirectly via regulation of GLP1 and GIP secretion. Although there is still controversy whether mice with GPR40 deletion are protected from high fat diet–induced insulin resistance, current evidence for developing GPR40 agonists to treat type 2 diabetes outweighs that supporting the development of antagonists. This is further supported by the observation that loss-of-function mutations of the GPR40 gene in humans are associated with altered insulin secretion (Poitout lecture).

I- Regulation and maintenance of beta-cell mass
II – Regulation and production of insulin
III- Factors underlying beta-cell dysfunction in type 2 diabetes
IV- New tools in research and their clinical interest