Diet Composition and Physical Inactivity on Insulin Sensitivity and β-cell Function

It is well known that insulin resistance increases the risk of cardiovascular disease and
type 2 diabetes, which substantially impact mortality and morbidity and presents a
significant economic burden. Energy restriction with or without exercise has been
demonstrated to attenuate/reverse the development of insulin resistance and reduce the risk
of cardiovascular disease and type 2 diabetes. Indeed, accumulating evidence suggests that
diets high in protein may possess additional protection against the development of insulin
resistance during energy restriction. Layman et al. found that a high protein diet (HP) (PRO
125 g/d) compared with an isocaloric high carbohydrate diet (HCHO) (PRO 68 g/d) resulted in
greater reductions in fasting glucose and 2 h postprandial insulin levels during 16 weeks of
energy restriction in overweight women. Similarly, a hypocaloric high protein diet (PRO 45%
vs 20%; 21 d diet treatment) increased glucose oxidation and improved insulin sensitivity
compared to an isocaloric high carbohydrate diet during a euglycemic hyperinsulinemic clamp
procedure. In addition, markers of inflammation, β-cell function, and postprandial glucose
and insulin levels were improved in addition to increased resting energy expenditure after 6
months of hypocaloric HP compared with HCHO diet in premenopausal women independent of weight
loss. The increase in REE and improvement in adipose tissue function may be a potential
mechanism by which HP diet improves β-cell function since NEFAs are lower, which may reduce
lipotoxicity on the pancreas.

It is evident that physical inactivity (highlighted from bed rest studies) impairs glucose
tolerance, insulin sensitivity, vascular function, and muscle protein synthesis in both
healthy and obese individuals. This model of inactivity, however, is extreme and does not
recapitulate the physical inactivity paradigm seen in the natural human environment.
Consequently, a less extreme reduction in daily physical activity (>10,000 steps/d to ~1,500
steps/d) results in significant reductions in insulin sensitivity, glucose tolerance, and
insulin-stimulated muscle Akt phosphorylation, suggesting that the impairments in insulin
sensitivity and glucose tolerance precede changes in body composition. A reduction in
ambulatory activity is a highly valid and translatable model to study the role of inactivity
on the development of metabolic disease, as most individuals go through periods of
inactivity, and it has been shown that a reduction in daily steps decreases insulin
sensitivity and increases visceral adiposity. To date, no study has tested the effects of
diet composition on the perturbations of physical inactivity. It is important to know if
increasing protein intake mitigates the negative perturbations of reduced ambulatory
activity.

Thus, the overall objective of this project is to determine the extent to which short-term
high protein (HP) feeding may protect against the metabolic perturbations of physical
inactivity (i.e. PPG, hyperinsulinemia, and insulin sensitivity). The investigators will also
examine measures of vascular function and free living blood pressure in addition to lipemic
responses (i.e. FFAs, triglycerides, cholesterol, and lipoproteins) to determine if HP diet
impacts vascular function and lipemic responses during short term physical inactivity.

Trial Objectives and Purpose

The specific aims of this project include the following:

Specific Aim 1: To determine if HP diet during a period of low physical activity will lower
the insulin response to a meal, and help to maintain insulin sensitivity and β-cell function
during a laboratory based mixed meal test (MMT) with stable isotope tracers.

Specific Aim 2: To determine if a HP diet during a period of low physical activity will
maintain glycemic control measured by continuous glucose monitoring (CGM) in healthy,
recreationally active, young individuals.

Inclusion Criteria:

1. BMI <28 kg/m2

2. No known cardiovascular, kidney, or liver disease.

3. No history of surgery for weight loss and weight stable for prior 3 months (weight
change < 3 kg).

4. Physically active individual (90 minutes of primarily whole body aerobic physical
activity <3 days per week and taking greater than 10,000 steps per day)

5. Between 18-45 yr of age.

6. Participants who consume on average less than 18% of total calories as protein

Exclusion Criteria:

1. History of alcohol use (< 20 g/day for males and > 10 g/day for females)

2. Smoker.

3. BMI < 28 kg/m2

4. Kidney or liver disease.

5. Physically inactive (completing < 75 min of whole body aerobic activity <3 times per
week or obtaining <10,000 steps/day)

6. Pregnant or lactating

7. <18 or >45 yr of age

8. High protein consumers (>20% of total daily calories as protein)