• Aucun résultat trouvé

Role of the circadian clock in the pathology of Type 2 diabetes (T2D)

3.2. Central and the peripheral clocks

3.6.3. Role of the circadian clock in the pathology of Type 2 diabetes (T2D)

difficulties to lose weight and presented higher plasma ghrelin concentration as well as alterations of eating behaviour [80].

REV-ERBα became a new lead to follow in the understanding of obesity mechanisms.

Indeed, two studies have established a relationship between SNP of REV-ERBα and obesity in two independent populations (Mediterranean and North American) [81,82]. In obese women with metabolic syndrome, the expression of REV-ERBα in adipocytes was positively correlated with waist circumference and Body Mass Index (BMI) [83]. Therefore, REV-ERBα plays an important role in the pathology of obesity and metabolic syndrome.

3.6.3. Role of the circadian clock in the pathology of Type 2 diabetes (T2D)

In physiological conditions, food-induced hyperglycemia induces insulin secretion by beta cells via the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, leading to increased glucose uptake by skeletal muscle and adipose tissues, and to a reduction in hepatic glucose production. In case of hypoglycemia, glucagon is secreted to increase glycemia level by stimulating liver neoglucogenesis and glycogenolysis through the protein kinase A pathway (PKA) [84,85]. In case of T2D, the chronic exposure to glucose combined with sedentary life style alters beta cell function and reduced insulin sensitivity. This leads to impaired insulin secretion and consequently hyperglycemia, a hallmark of T2D [86].

3.6.3.1. Mice studies on the connection between T2D and clock

The existence of an autonomous molecular clock in the endocrine pancreas was described in mouse and rat pancreas [87,88] but also in mouse islets [89] and in pancreatic cell lines like MIN6, INS-1 and αTC1-9 cells [90-92].

The essential study that highlighted the relationship between clock disruption and T2D in mouse model came out in 2010 by Joseph Bass and colleagues [89]. The researchers have

37 found that ClockΔ19/ Δ19 mutant mice had defect in islet proliferation and reduced islet size and function, resulting in reduced insulin release. Moreover, specific Bmal1-knockout mice in the pancreatic islet displayed impaired glucose tolerance, insulin secretion, and additional features of T2D phenotype [89]. These observations were confirmed in pancreas explants and beta cells in 2011 by Sadacca et al. They showed that Bmal1 pancreas-specific knock-out mice exhibited glucose intolerance and impairment of insulin production. Isolated islets from these mutant mice had normal insulin content but defect in glucose-stimulated insulin secretion [93]. The exocytosis of insulin granules was blocked in beta cells of these mice [94,95].

Supporting this idea, Shi and al demonstrated in 2013 that wild type mice showed a circadian rhythm of insulin action with a more pronounced insulin resistance at Zeitgeber Time (ZT) 7.

The Bmal1-knockout mice were insensitive to insulin and the circadian phase of insulin action and glucose metabolism was comparable to the inactive daily cycle of WT mice [96]. Insulin resistance induced by HFD was associated with the disruption of the circadian expression of clock and lipogenic genes in mice liver [97]. Liu and al recently showed that CLOCK and BMAL1 activate SIRT1 to improve muscle insulin sensitivity in mice [98].

The implication of REV-ERBα in glucose homeostasis has been recently demonstrated.

Knockdown of Rev-erbα in alpha cells inhibited low-glucose induced glucagon secretion while agonist of Rev-erbα increased glucagon secretion. The effect on glucagon secretion was mediated by the AMPK/Nampt/SIRT1 pathway since inhibition of Nampt decreased Sirt1, Pgc1 and Rev-erbα expression [92]. In mouse pancreatic islets, inhibition of Rev-erbα impaired glucose-induced insulin secretion and beta cell proliferation [91]. In mouse white adipose tissue, Rev-erbα modulates the activity of FGF21 by binding to its co-receptor βKlotho [99]. FGF21 is known to increase insulin sensitivity and to prevent hepatitis steatosis [100].

38 Cryptochrome proteins were also related to glucose metabolism. Over-expression of Cry1 in liver of diabetic mice (db/db) improved insulin tolerance and decreased glycemia [101]. In addition, Cry1 and Cry2 inhibited C-AMP response element-binding protein (CREBP) phosphorylation by blocking G protein-coupled receptor (GPCR)-mediated increase in cAMP signaling during fasting in the liver. This resulted in the inhibition of gluconeogenesis, therefore a decrease in glycemia [101].

The connection between circadian clock and glucose metabolism is reciprocal. As stated above, functional circadian clock is indispensable for regulating glucose metabolism. On the other hand, the concentration of glucose is feeding back on the clock machinery. For instance, the effect of glucose concentration on the modulation of the clock machinery was described by Li and al in 2013. The expression of BMAL1 in U2OS cells was higher when the cells were subjected to a high concentration of glucose (25 mM) compared to the cells submitted to a low glucose concentration (5 mM). The authors demonstrated that the hexosamine / O-GlcNAc pathway modulated the circadian clock since OGT over-expression modified the phase of BMAL1 and CLOCK expression. The manipulation of hepatic OGT expression in mice resulted in aberrant rhythm of glucose homeostasis [55].

Metformin is an oral anti-diabetic drug commonly used to treat T2D patients, and is a modulator of the molecular clock. In mice, metformin has been shown to advance the phases of Clock, Bmal1 and Rorα in the liver by activating the AMPK pathway [102].

3.6.3.2. Explorations in humans

In humans, the impact of sleep-deprivation on metabolic dysregulations has been clearly established. Shift-working accelerates the development of metabolic syndrome and increases the risk of cardiovascular diseases [103-105]. A large population-based study including men and women shift workers demonstrated that men shift-workers had higher BMI and waist

39 circumference whereas women shift-workers increased their glycemia and HbA1c levels [106]. Long term shift-working has also been associated with increased risk of breast cancer, and its morbidity [107,108].

It prompted the researchers to take a close look at possible interactions between the circadian clock and the metabolism in humans.

The analysis of SNP from core clock genes and CCGs revealed a strong correlation between NPAS2 (Neuronal Clock) and hypertension, and PER2 was associated with high fasting glycemia [109]. In T2D patients, a Clock SNP was associated with an increased risk of stroke, suggesting a contribution of clock genes into cardiovascular risk in T2D patients [110].The existence of cell-autonomous circadian oscillator in human islets has been demonstrated for whole pancreatic islets and dispersed islet cells. Indeed, clock transcript expressions were following circadian pattern in human pancreatic islets and dispersed cells synchronized in vitro [111]. Furthermore, it has been shown that functional clock is indispensable for proper insulin secretion by human beta cells [112].

With respect to connection between circadian clock and T2D, the expression levels of PER2, PER3 and CRY2 transcripts in human islets isolated from T2D donors were lower if compared to healthy counterparts [113]. Of note, the mRNA levels of these genes were positively correlated to the insulin content, while PER3 and CRY2 transcript levels were negatively correlated with glycated hemoglobin level (HbA1c). In line with these findings, the mRNA expression levels of BMAL1, PER1 and PER3 were lower in leucocytes of T2D patients.

Moreover, HbA1c levels were inversely correlated with transcript expression in the same subjects [114].

The following study by Pivovarova and colleagues has established a clear relation between dietary change and clock machinery. The researchers induced a switch of diet in healthy

40 subjects from 6-weeks high carbohydrates-low fat diet to 6-weeks low carbohydrate-high fat diet. After the switch, the oscillations of period genes in monocytes of the subjects were altered, as well as the genes involved in inflammation and fat metabolism [115]. The same group studied the relationship of weight loss and gene expression in subcutaneous adipose tissue applying similar experimental design. Increase of PER2 and NR1D1 expression has been detected following the weight loss. Moreover, a correlation between the expression levels of core clock genes and those implied in fat metabolism, autophagy and inflammation has been reported [116].

To conclude, there is a reciprocal connection between circadian clock and metabolism.

Mutations of clock genes might have a negative impact on glucose and lipid metabolism, but the reverse might be also true. Diet enriched with fat and carbohydrates altered the cellular clock and a change of diet influence the expression of clock genes.