Chronotype of Patients With Diabetes and Effect on Glycaemic Control

The aim of this study is to explore the associations between chronotype and glycaemic control, cardiometabolic health and other lifestyle factors.

The incidence and prevalence of diabetes mellitus has now reached over 5 million in the United Kingdom (UK). Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of the UK population with diabetes and is a condition characterised by hyperglycaemia, resulting from defects in hepatic and peripheral glucose uptake, insulin secretion, or both. Conversely, around 8% of those diagnosed with diabetes, have Type 1 diabetes mellitus (T1DM). This equates to \~400,000 people in the UK. The incidence of new diagnoses of T1DM is also increasing by about 4% each year, with around half of these being in people over the age of 18. T1DM is caused by an autoimmune reaction where the body's defence system attacks the cells that produce insulin. As such, T1DM requires life-long treatment with exogenous insulin therapy accompanied by blood glucose monitoring.

Regardless of type, there is an increased vulnerability to microvascular (nephropathy, neuropathy, and retinopathy) and macrovascular complications (coronary artery disease, peripheral arterial disease, and stroke). As a result, new paradigms for characterising and treating these patients could enhance current and future diabetes management.

Recently, there has been considerable interest in the association between quantity and quality of sleep and circadian rhythms and the development and management of cardiometabolic disease especially metabolic syndrome, diabetes and Cardiovascular Disease (CVD). A "U"-shaped relationship related to both short and long sleep duration exists between sleep duration and diabetes, obesity, CVD, hypertension and stroke. A meta-analysis of nearly 500,000 individuals (\~4% T2DM) identified a relative risk (RR) of 1.14 (95% CI 1.03-1.26) for every additional hour of sleep and RR 1.09 (95% CI 1.04-1.15) with each hour of shorter sleep compared to 7-hours sleep per day for the development of T2DM. Despite this many individuals do not consider sleep essential for good health but instead consider it to be rather more of an inconvenience. Subsequently, lifestyle choices, societal pressures and shift-work render the population chronically sleep deprived and thus at increased risk of metabolic dysfunction.

Sleep is regulated, in part, by a homeostatic drive and is therefore unavoidable in humans (without sleep disorders). The circadian system, our internal clock, is also responsible for the regulation of sleep. Sleep is a multidimensional behaviour (and biological process) where we need to not only consider duration and quality but timing also. A person's sleep pattern, in relation to the 24-hour clock, i.e. timing, is individual to them and referred to as their chronotype. We can quantitatively characterise these individual differences in daily timing using a number of questionnaire based tools.

Five different chronotypes have been identified using the 'Morningness-Eveningness' Questionnaire i.e. definite evening type, moderate evening type, intermediate, moderate morning type and definite morning type. The identification of these different chronotypes, which describes preferred circadian phases, into, at the two extremes, "morning type" and "evening type" has led to further research confirming that "evening types" are at greater risk of cardiometabolic disease and metabolic dysfunction. The underlying causes have not been clearly defined but appear to be related to circadian mal-alignment causing chronic sleep deprivation and leading to dysregulation of metabolic, immune and hormonal processes that govern energy regulation and glycaemic control.

Several clock genes have been identified in the control of circadian rhythms including Clock (Circadian locomotor output cycles protein kaput), Npas2 (Neuronal PAS domain protein2), Bmal1 (Brain and muscle ARNT-like protein), Per1 (Period), Per2, Per3, Cry1 (Cryptochrome), Cry2, Rev-Erbs (Reverse erythroblastosis virus) and CkI (Casein kinase). However their role if any, in progression in diabetes remains to be elucidated.

The concept of "social jetlag" has been developed to describe the deleterious effects of chronic sleep deprivation related to weekday occupational obligations on "evening types" and weekend social demands on "morning types". For example, a large epidemiological study in Germany has shown that social jetlag is associated with obesity. Several public health questions are raised by these associations, not least whether chronotyping of all individuals should be considered and whether the individual chronotype can be adjusted by sleep hygiene and training (which requires discipline for maintenance) and/or exogenous treatment with melatonin.

In this cross-sectional observational study, we therefore propose to extensively chronotype a sample of patients with T1DM and T2DM to determine the impact of chronotype on glycaemic control, insulin resistance, biochemical profile, and inflammatory, adipocytokine and genetic markers using a validated questionnaire and blood tests.

In an optional sub-study, we will explore the association between diabetes, chronotype and objectively measured physical activity, energy intake, clock genes and well-being. We will also offer participants the opportunity to wear a continuous glucose monitor. Those that have consented to take part in the optional sub-study, and to be contacted about future ethically approved research, will also be offered the opportunity to have these measurements repeated at a later date.

Eligibility Criteria:
Inclusion Criteria:

1. Participant is willing and able to give informed consent for participation in the study
2. T1DM or established T2DM (\>6months since diagnosis)
3. Male or Female
4. Aged 18-75 years inclusive
5. BMI less than or equal to 45kg/m² inclusive
6. No known sleep disorders except Obstructive Sleep Apnoea (OSA)
7. On any glucose-lowering therapy (T1DM or T2DM) or lifestyle modification for management of T2DM
8. Good command of the English language

Exclusion Criteria:

1. Participant is unwilling or unable to give informed consent
2. Anyone without a good command of the English language
3. Anyone \<18 years of age and \>75 years of age
4. BMI greater than 45 kg/m²
5. A regular cannabis user i.e. weekly use
6. Have a terminal illness
7. A known sleep disorder that is not OSA
8. Regular use of the following medicines i.e. Weekly use: (Wakefulness promoting agents Modafinil, Amphetamine derivatives, Methylphenidate; Sedatives including benzodiazepines, Z-drugs (zopiclone, zolpidem \& zaleplon); Melatonin, including Circadin and melatonin analogues; Clonazepam and other drugs for nocturnal movement disorders).