GLP-1 is an anorexigenic amino acid pro-hormone secreted mainly in the distal ileum and the colon. Typical fasting plasma concentrations range from 5-10 pmol/l, increasing 2-3 times after food (Mansour et al., 2013). GLP-1 administration reduces food intake in healthy weight and obese individuals. It inhibits gastric acid secretion, slows gastric emptying and supresses glucagon release (Diakogiannaki et al., 2012), and has direct effects on the CNS to decrease food intake and increase energy expenditure (Zhang et al., 2010). GLP-1 increases insulin secretion in a glucose-dependent manner by binding to receptors on pancreatic β cells. It can increase β cell mass by stimulating proliferation and may indirectly decrease glucagon secretion via the paracrine effect of insulin on α cells (Zhang et al., 2010).
Studies have shown that GLP-1 elimination is similar in healthy, obese and T2DM, however, postprandial concentrations were lower in OW and T2DM suggesting GLP-1 secretion is attenuated in these metabolic states (Mansour et al., 2013). Lower plasma GLP-1 levels observed in T2DM were the same in well- controlled and poor-glycaemic controlled patients, suggesting T2DM per se did not affect GLP-1 secretion (Diakogiannaki et al., 2012).
Mingrone et al. (2009) reported circadian rhythms of GLP-1 in morbidly obese T2DM patients and normal controls with acrophase times of 07:22 h and 17:56 h, respectively. Although cosinor analysis revealed a daily rhythm, there was no indication the participants were synchronised before entry into the study or exogenous confounders were controlled during the laboratory session. Thus, the observed rhythm was not necessarily truly circadian and may have been due to endogenous and exogenous factors. Morgan et al. (1998) reported inconsistent postprandial levels in plasma GLP-1 with no evidence of a circadian rhythm using a CR protocol.
1.4.7 Ghrelin
Ghrelin is an orexigenic hormone produced mainly in the stomach and the pancreas. Fasting plasma acetylated ghrelin (AG) levels are similar in pre-diabetes and T2DM and lower than in normoglycaemic individuals (Sharifi et al., 2013).
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Ghrelin seems to have two components to its metabolism, firstly, circulating concentrations increase when nutrient levels are low to stimulate appetite and secondly, rise throughout the day and peak in the middle of the night. In a controlled laboratory study where participants were given three meals a day, ghrelin concentrations rose before the meal and decreased sharply within 60 minutes post-meal. Insulin concentrations followed a similar pattern, peaking 60 minutes after the meal, although there was a wide inter-individual variability (Cummings et al., 2001). In this study, leptin was also measured and although the decrease in concentration was at the same time as insulin, it was not as precipitous as ghrelin or insulin. After the last meal at 17:30 h, ghrelin and leptin levels rose, both hormones reaching a peak at 01:00 h. The similar peak times of these hormones is intriguing as they have opposing effects on metabolism; ghrelin is a hunger hormone and stimulates appetite, whereas leptin is a satiety hormone.
Ghrelin levels are positively correlated with insulin sensitivity and have significant inverse relationship with circulating insulin (Purnell et al., 2003). Moreover, insulin has been proposed as a long-term mediator of ghrelin regulation; as insulin concentrations rise in response to a meal, ghrelin levels decrease (Saad et al., 2002). Excluding the meal effect, circulating ghrelin levels have a similar diurnal pattern to leptin. Ghrelin levels rise throughout the day reaching a peak at 01:00 h with a nadir at 06:00 h (Cummings et al., 2001). Lower leptin and raised ghrelin levels have also been associated with short sleep and could explain the higher BMI observed with short sleep duration by increasing appetite (Taheri et al., 2004).
There is evidence to suggest that the circadian clock plays a role in ghrelin regulation and that ghrelin may also be produced within the mediobasal hypothalamus (MBH)/subparaventricular nuclei (SPV). In a study examining obesity and metabolic syndrome in mice, ghrelin mRNA expression was reduced in the MBH in Clock mutant mice at virtually all time points of the 12L:12D cycle (Turek et al., 2005).
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1.4.8 Leptin
Leptin is an anorexigenic hormone produced in adipocytes, skeletal muscle and the stomach; the physiological effects from these different organs are thought to be the same (Zhang et al., 2010). Gastric-derived leptin is secreted into the gut lumen (Buyse et al., 2001) and constitutes 25% of circulating levels. Leptin suppresses appetite by sending satiety signals to the brain and increases glucose uptake into cells in response to food (Zhang et al., 2010).
There is a direct relationship between plasma leptin and body weight, thought to be due to the increased adipose tissue mass increasing leptin secretion. As well as higher circulating levels of leptin, dampened diurnal rhythms and reduced relative amplitude in obesity may contribute to leptin resistance in obesity (Saad et al., 1998). Fasting plasma leptin was not reported to be associated with T2DM (Sharifi et al., 2013).
Leptin has a daily rhythm, which peaks around 00:00-02:00 h. Under normal sleep-wake conditions (23:00 – 07:00 h) leptin peaks at 02:04 h (Benedict et al., 2012). Maentele et al. (2012) showed that leptin had a clear daily rhythm, peaking at 00:31 h, which was not affected by obesity or T2DM. Cummings and colleagues showed that leptin displayed a clear diurnal variation with a nadir at 09:00 h and peak at 01:00 h (Cummings et al., 2001).
The peak time and amplitude of leptin rhythms are affected by sleep status (Spiegel et al., 2004). In young healthy adults, controlled for energy intake and expenditure, leptin levels were 19% lower in the sleep restricted group (01:00- 05:00 h) compared to those with a 12 h sleep opportunity (21:00-09:00 h). The dampened rhythm in the sleep debt group also peaked 2 h earlier than in the extended sleep group, 21:30 h ± 43 mins vs 23:30 ± 21 mins. However in another study, leptin concentrations did not change dramatically in response to feeding, only showing an 8-9% drop in circulating levels within 1 h of consuming a meal (Benedict et al., 2012).
In a study examining the effect of meal timing on leptin levels in humans, leptin rose during the evening with an amplitude of 21%, peaking at 24:00 h, and nadir between 09:00 and 12:00 h (Schoeller et al., 1997). When the meals were
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shifted by 6.5-h without changing the light or sleep cycles, the plasma leptin rhythm was shifted by 5-7 h. The phase shift occurred rapidly when compared with changes in the diurnal rhythm of cortisol, suggesting that the circadian clock does not solely drive diurnal leptin rhythms.
1.4.9 Resistin
Resistin is produced mainly in adipocytes in rodents, however, it is secreted by macrophages in humans making comparison between the effects of resistin in animal models to humans more complex (Cao, 2014). In mice it acts as a signalling molecule, activated by adipogenesis; higher levels observed in diet-induced obesity have opposing effects to insulin, and thus increase insulin resistance (Steppan et al., 2001).
Epidemiological studies have linked higher circulating resistin levels with increased risk of T2DM (Burnett et al., 2006). Secretion of resistin by macrophages in humans has led to the belief that it is more closely associated with chronic inflammation than with obesity and T2DM per se. The higher levels of circulating and adipose tissue resistin in obesity may be a result of greater infiltration of macrophages into the adipose tissue. Although in many studies there was no association with adiposity, in some studies resistin levels dropped after weight loss but in other studies there was no change (Park and Ahima, 2013). Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation (Park and Ahima, 2013). Although conflicting results have been reported in the literature, higher baseline levels of circulating resistin have been observed in T2DM patients and have been significantly correlated with increased risk of T2DM after adjustment for other risk factors (Park and Ahima, 2013).
Higher circulating resistin concentrations in shift workers, independent of age, BMI, waist-hip ratio, HOMA and cardiovascular risk have been reported and may provide a link between resistin and circadian misalignment (Burgueno et al., 2010). Resistin concentrations measured over 24 h showed that circulating resistin levels did not display any daily variation (Aziz et al., 2011).
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1.4.10 Visfatin
Visfatin also named nicotinamide phosphoribosyltransferase (Nampt) and pre-β- cell colony-enhancing factor (PBEF), is produced mainly in visceral adipose tissue (Dogru et al., 2007), but also in skeletal muscle and liver (Benedict et al., 2012). Plasma concentrations are higher after a night of sleep deprivation (Benedict et al., 2012). Esteghamati et al. (2011) observed no correlation between serum visfatin and BMI or waist circumference. By contrast, Friebe et al. (2011) reported higher visfatin levels in children with obesity and impaired insulin.
Fasting morning plasma visfatin levels of newly diagnosed, non-medicated T2DM patients, were reported to be significantly higher than in healthy controls (Dogru et al., 2007). Higher fasting serum visfatin levels have been observed in T2DM patients than healthy controls which were also positively associated with the homeostatic model assessment (HOMA) insulin resistance index (Esteghamati et al., 2011). Up to 2000 mg metformin given to T2DM patients for 12 weeks did not have a significant effect on plasma visfatin levels (Erdem et al., 2008).
Under a regular sleep-wake pattern of eight hours (23:00 – 07:00 h), visfatin peaks in the afternoon (15:53 h) (Benedict et al., 2012). In this study, a night of sleep deprivation caused the visfatin rhythm to phase advance by 2 hours, peaking at 13:37 h. Fasting serum visfatin levels were higher in individuals who slept more than 7 hours, compared to those sleeping less than 5.5 hours a night (Hayes et al., 2011).