Asian Indian Prediabetes Study

Compared to other races, Indians have higher insulin resistance, poorer pancreatic function and a greater risk of developing diabetes, highlighting the importance of early strategies for improving insulin sensitivity and improving pancreatic function in Indians to prevent diabetes and lower the risk of heart disease.

A low carbohydrate diet can deplete fat from undesirable places, such as fat around organs in the abdominal cavity. In this study, we will determine if restriction of dietary carbohydrates will deplete fat in the pancreas and liver, and improve insulin sensitivity and early insulin secretion in Indians. These changes may prevent diabetes from developing. Hepatic and pancreatic fat will be measured using magnetic resonance imaging. Insulin sensitivity and secretion will be measured during an oral glucose tolerance test. In addition, this study will investigate if the higher insulin resistance in Indians is due to genes that cause the inability to store fat in the legs.

The results on the type of diet that is more effective for reducing pancreatic and hepatic fat is important for informing dietary guidelines on the use of low carbohydrate diets for diabetes prevention, particularly in Indians who have a higher risk of developing diabetes.

Compared to other races, Indians have a greater risk of developing type 2 diabetes (T2D), increased insulin resistance (IR) and more rapid decline in β-cell function, highlighting the urgency and importance of early intervention strategies for improving insulin sensitivity and preserving/improving β-cell function to prevent T2D and mitigate against the increased vascular disease risk.

Preliminary findings show a reduction in glycemic load selectively depletes visceral and ectopic lipid and improves insulin sensitivity and β-cell function in non-diabetic adults. The proposed research will investigate if the phenotypic features increasing T2D risk in individuals of Indian ancestry (IR and impaired β-cell function) can be favorably modified by a low glycemic (LG) intervention, and if the increased IR is attributable to genetic factors regulating adipocyte differentiation and function.

These research objectives will be achieved through a 24-week randomized controlled trial (RCT) comparing isocaloric LG versus control diets in Indians with prediabetes. Compared to individuals in the control group, those on the LG diet are expected to have greater ectopic (pancreas, liver, visceral and intramyocellular) fat depletion assessed with MRI/MRS, and improvements in first phase insulin secretion and insulin sensitivity assessed with the C-peptide model and oral minimal model, respectively during an OGTT. Reductions in hepatic and pancreatic lipids will be associated with improvements in first-phase β-cell response. Individuals with a greater number of risk alleles from a 53-SNP IR genetic risk score will have lower insulin sensitivity and leg fat, supporting the notion that impaired adipocyte differentiation leading to limited peripheral adipose expansion capacity is an important etiological factor underpinning IR cardiometabolic disease in Indians.

The results will broaden the evidence base for effective prevention strategies in this high risk population by investigating the effect of the proposed diet intervention on underlying physiological and molecular mechanisms implicated in the pathophysiology of T2D in Indians.

Eligibility Criteria:
Inclusion Criteria:

* Male or female
* Asian Indian ethnicity
* Age between 21-50 years
* BMI not greater than 35 or less than 25
* Prediabetes (based on results from an OGTT conducted in the last 3 months):

  * Impaired Fasting Glucose (IFG) which is a fasting blood glucose level of between 5.6 to 6.9 mmol/l and/or
  * Impaired Glucose Tolerance (IGT) which is a blood glucose level of 7.8 to 11.0 mmol/l, 2 hours after the OGTT but below 7.0 mmol/l in the fasting state.
* Not have type 1 or type 2 diabetes
* Not on any diabetes medications that affect insulin sensitivity e.g. metformin, glitazones
* No abnormality of clinical significance on medical history
* If female, not pregnant or breast feeding
* No history of coronary artery disease or cardiac (heart) abnormalities
* Participants must understand the procedures involved and agree to participate in the study by giving full informed, written consent

Exclusion Criteria:

* BMI greater than 35 or less than 25
* Weight gain or loss of more than 5% over the past 3 months
* Have anaemia (low haemoglobin/ red blood cell levels), a malignancy (cancer), abnormal liver function, any significant endocrinopathy (e.g. thyroid problems), or a history of metabolic disease such as liver, kidney, cardiovascular, respiratory or gastrointestinal disease.
* Have high uncontrolled hypertension (resting seated blood pressure \>160/100 mmHg)
* Taking medications that may affect glucose metabolism e.g. steroids, thiazide diuretics at doses\>25mg/day.
* History of smoking or using nicotine products during the 6 months prior to study
* History of heavy alcohol consumption (\> 5 standard drinks/day)
* Inability to limit alcohol consumption for study duration
* Lactose Intolerant or have a nut allergy
* Have depression
* Have a musculoskeletal injury, joint or peripheral vascular disease sufficient to impede exercise (such as hip arthritis, foot, ankle problems or pain)
* Have severe exercise-induced asthma
* Participating in a regular aerobic or resistance exercise program
* Currently on a weight reducing diet or have an eating disorder
* Contraindications for MRI e.g. if you have certain metallic implants/devices such as heart valves of a cardiac pacemaker which may be affected by the magnetic field
* Unwilling to be randomized to either diet group
* Extended absences due to travel or other commitments
* Unable to comprehend or cope with study requirements