This study is undertaken to explore in T2D, the effect of meal timing on serum induced SIRT1 and Clock Genes mRNA expression in cultured hepatocytes. Fasting serum samples were collected from T2D participants, following two different meal timing schedules, either a diet with large breakfast and lunch with small dinner Breakfast Diet (3Mdiet) or an isocaloric diet with 6 small meals evenly distributed along the day Allday Diet (6Mdiet). The researchers will use an ex-vivo/in-vitro approach in which cultured medium will be conditioned with the fasted human serum collected from the two groups of T2D participants at baseline, after 2 weeks and after 12 week of the diet intervention.

The timing of many physiological processes, including glucose metabolism, is coordinated by the circadian clock gene system. The circadian clock regulation, optimize glucose metabolism for the consumption of high energy and carbohydrate (CH) meals in the early hours of the day and for fasting at evening and night. Circadian disruption which occurs when the meal timing is not aligned with the circadian clock rhythms like skipping breakfast, overeating CH at night or eating CH all day, lead to desynchronized clock genes and can result in adverse health outcomes like insulin resistance, obesity hyperglycemia and T2D. Although the clock genes are disseminated in almost all peripheral tissues, those localized in the liver, are particularly important for the regulation of glucose metabolism, influencing the enzymatic determinants of the hepatic glucose output, by enhancing glycogen storage and suppressing nocturnal hepatic glucose production (glycogenolysis and gluconeogenesis sequentially).Therefore, the disruption of the hepatic clock genes lead to fasting, nocturnal, and to postprandial hyperglycemia in T2D. The researchers had previously shown in T2D, that compared to 6Mdiet, the 3Meal diet timing schedule, was most effective in reducing body weight, HbA1c, overall hyperglycemia, and led to up-regulation of SIRT1 and Clock Genes mRNA expression in leukocytes. However, this effect of meal timing had never been explored in liver cells. The investigators hypothesized that compared to Allday Diet (6Mdiet), the serum collected from T2D participants following Breakfast Diet (3Mdiet) will up-regulate SIRT1 and Clock Genes oscillatory mRNA expression in cultured hepatocytes.

Inclusion Criteria:

• T2D patients with stable treatment for at least 3 month preceding the study.
• HgA1c >7.5 %.
• Age > 30 years.
• BMI: 27-34 kg/m2.
• Treatment with antidiabetic drugs (i.e. metformin, DPP4 inhibitors, glinides) and GLP-1 analogs, will be allowed
• Anti-hypertensive treatment will be allowed.
• Lipid-lowering medication also allowed

Exclusion Criteria:

• Type 1 diabetes.
• Major illnesses (liver, heart, kidney, infectious, neurological, psychiatric, immunological, active malignancy).
• Change in weight of > 4.5 kg within 3 month prior the diet onset.
• Night or rotating shift workers.
• Those who crossed more than 2 time zones during 2-week period prior to study onset.