Type 2 Diabetes Mellitus (T2DM) and Intermittent Fasting (IF)

Type 2 Diabetes Mellitus (T2DM) poses a significant global health challenge. It is estimated that about 10% of the adult population globally (20 to 80 years old) suffers from Diabetes, and of those, T2DM makes up a vast majority (~90%).

T2DM tends to be characterized particularly in terms of its manifestation as hyperglycemia, insulin secretion deficiencies, and insulin resistance. Its progression involves chronic hyperglycemia that leads to β-cell dysfunction, a reduction in β-cell mass and identity, and their dedifferentiation.

While the interplay of genetic and environmental factors in Type 2 Diabetes Mellitus (T2DM) is increasingly better understood, role of certain non-pharmacological interventions, such as Intermittent Fasting (IF), in influencing the pathways at a metabolic level are not yet established, primarily due to a lack of diverse studies.

IF, commonly adopted for weight loss, has been observed to confer metabolic benefits such as reduced blood glucose levels, enhanced insulin sensitivity, decreased adiposity, reduced inflammation and oxidative stress, alongside increased fatty acid oxidation, thereby reducing visceral fat and achieving an overall weight loss. Weight loss in itself is effective in managing DM upto a certain extent.

The challenge lies in distinguishing the direct effects of IF on the complex pathophysiology of T2DM, beyond the general benefits of weight loss and lifestyle changes.

Gaps in existing research studies:

• The current body of research on Intermittent Fasting (IF) as a therapeutic approach for T2DM predominantly relies on animal models and data from American populations, which limits its applicability to other populations such as Asians, who have distinct dietary habits, due to lack of diversity and relevance to human physiology.

• Most existing Randomized Controlled Trials (RCTs) on the metabolic effects of IF also exclude patients with diabetes, leading to a significant gap in understanding IF's effects in this key demographic.

Asian Indians are an ethnic group highly susceptible to type 2 diabetes, with some of the most significant increases in diabetes prevalence occurring in this region. Type 2 diabetes manifests differently in Asian Indians compared to white Caucasians in several key aspects:

• a) Asian Indians generally develop diabetes at younger ages and with lower obesity levels.

• b) Additionally, they transition more quickly from pre-diabetes to full-blown diabetes compared to other ethnic groups.

• c) The 'Asian Indian phenotype,' marked by high abdominal fat and elevated insulin resistance at lower BMI levels, is thought to contribute to this heightened diabetes risk.

• d) Furthermore, recent research indicates early and rapid beta-cell dysfunction in Indians.

Thus, the primary cause of T2DM in this group appears to be severe insulin deficiency occurring earlier, contrasting with the obesity-driven insulin resistance predominant in white Caucasians.

This means the efficacy of IF for the treatment of T2DM in this group needs to be re-evaluated. We believe it is important to recognize that patients in India differ phenotypically to the typically predominantly caucasian studies for investigating efficacy of IF, and that this variation impacts on their risk of complications.

This project proposes a comprehensive RCT that includes a diverse participant pool, encompassing different social groups, dietary patterns, and importantly, individuals with T2DM.

We will

Aggregate and analyze existing scientific literature on different proposed mechanisms for Type 2 Diabetes Mellitus (T2DM).

• Our approach will include a methodical search and synthesis of peer-reviewed studies.

• Through this comprehensive review, we aim to construct a detailed, evidence-based landscape of T2DM research, particularly focused on IF’s effects and what particular mechanisms might be studied.

• Employ meta-analytic techniques to quantitatively assess the impact of lifestyle modifications and technological interventions in T2DM management.

Conduct a Randomised controlled trial to evaluate:

• The impact of IF on glycemic markers, BMI, and blood pressure for this group of ethnic population.

• Compare IF with continuous energy restriction on glycemic control.

• Determine optimal IF duration for T2DM reversal and long-term effects.

Methodology for the study:

Design: Randomized controlled trial based on CONSORT 2010 guidelines.

Study Population: 120 eligible participants from Guru Nanak Dev Hospital, Amritsar (a tertiary level health care center)

Duration: 20 weeks (~5 months)

Selection Criteria: Adults (25-65) with HbA1c (5.7-8%), BMI > 25 kg/m², not on prior anti-diabetic medications.

Procedure: Stratified random sampling into fasting and control groups. Fasting group follows 16:8 IF protocol while the control group receives daily calorie restriction. Comprehensive counseling and follow-ups ensure compliance and monitor health parameters.

Ethical Considerations:

• Institutional Ethics Committee approval shall be sought.

• Informed consent and confidentiality will be maintained.

India is a country with a large population living with subpar access to healthcare treatment, with poor socioeconomic incentives and infrastructure to provide them with the care they need. The sheer spread of diabetes in the country is alarming, especially when combined with younger people getting severe diabetes early in life. We believe that pursuing this line of research will significantly contribute to the understanding of IF as a viable non-pharmacological intervention for T2DM, which would be very cost-effective in a low-mid income country such as India.

Outcomes:

How will this funding be used?

1. Recruiting and screening approximately 120 participants.

2. Covering expenses related to participants' time, travel, and dietary resources as a form of reimbursement for their involvement in the study.

3. Funding will be used for regular laboratory tests and investigations, including parameters such as fasting blood glucose, fasting insulin, HbA1c, BMI, leptin, etc., conducted on a weekly basis for 5 months.

4. A portion of the grant will be used to provide a modest salary for myself.

5. Fees for publishing the research in journals, including open access