Lowering Impaired Fasting Glucose Levels With Exercise

In individuals with type 2 diabetes (T2D), chronically elevated glucose and insulin levels
result in numerous health complications. Maintaining tight glucose control is difficult for
individuals with T2D, particularly in the postprandial period and in the morning period just
prior to waking. In the postprandial period, the combined effect of insulin resistance and
beta cell dysfunction results in a prolonged elevation in glucose levels, and augmented
insulin levels in an attempt to reduce the circulating glucose levels. In the overnight
period, there is evidence of enhanced endogenous glucose production and of a disruption of
the interaction between glucose levels and insulin secretion. Early work in individuals with
T2D demonstrated that with continued fasting, glucose levels stopped declining in the evening
and subsequently rose throughout the night to reach a morning maximum, and this elevation
persisted till noon. Additionally these authors demonstrated that insulin levels and insulin
secretion rates did not parallel the nocturnal glucose changes in individuals with T2D, while
in the controls the nocturnal glucose and insulin secretion rates coincided. Evidence is also
emerging that hyperglucagonemia may be occurring in the setting of deficient insulin
secretion, and may be playing a role in the elevated postprandial glucose levels and in the
overnight period. These studies provide preliminary evidence that there is disruption in the
fine coordination between glucose levels and glucagon and insulin secretion, and that this is
exacerbated more in the overnight period than during the waking hours. Previous studies
examining the overnight period have been conducted following prolonged fasting (~24-34 h),
however, most people do not fast for extended periods of time prior to going to bed.
Additionally, individuals with T2D often know that meal composition the evening prior can
exacerbate the elevated fasting glucose levels the following morning, thus highlighting the
need to examine the effect of meal composition on overnight glucose control. To date, very
little is known about the pathology of why fasting glucose levels are elevated in many obese
individuals. There appears to be asynchrony between glucose and insulin levels in the
overnight period but very little research has focused on this phenomenon or how meal
composition affects overnight glucose levels. This study will provide evidence of potential
mechanisms for the elevation in overnight glucose levels and the findings will be
translatable for individuals with impaired fasting glucose (IFG) levels to understand the
importance of meal composition in the evening period.

The specific aims of this project are:

1. To examine the hormonal responses (glucagon, c-peptide, insulin, incretins) in response
to a meal in the postprandial period and the synchronization between glucose and
insulin/glucagon during the overnight period in non-obese individuals and obese
individuals with impaired fasting glucose levels (IFG).

2. To determine if the meal composition (standard meal: 55% carbohydrate, 20% protein, 25%
fat vs. high fat/fructose: 40% carbohydrate- 25% fructose, 40% fat, 20% protein) will
alter the hormonal responses (glucagon, insulin, incretin) in the postprandial period,
and if this change in meal composition will impact glucagon levels and glucose/c-peptide
synchrony in the overnight period.

Experimental design: Subjects will participate three times; 1) no exercise, 2) 2 hr post
dinner exercise, and 3) morning exercise (~7am). The order in which subjects undergo each
treatment will be randomized prior to study enrollment. Eligible subjects will initially
undergo baseline testing for assessment of body composition, exercise stress test and blood
screening. All subjects will have impaired fasting glucose levels. All subjects will undergo
3 study days that will start at ~1600 h and continue until 0700 h the following morning. They
will receive a standard meal (55% carbohydrate, 20% protein, 25% fat) at 1800 h and blood
samples will be taken from ~4:30 pm until 7 am.

Inclusion Criteria:

25-65 yrs of age body mass index (BMI): 30-45 kg/m2 for the obese subjects <24.5 kg/m2 for
the non-obese subjects weight stable during prior 6 months non-smokers OB with impaired
fasting glucose: elevated elevated morning fasting glucose levels >110 mg/dL for 5 of 7
days non-obese and OB subjects: fasting glucose levels < 100 mg/dL - 2hr OGTT glucose value
<140 mg/dL

Exclusion criteria overt cardiovascular disease sleep apnea surgical history for weight
loss use of weight-loss medications or active dieting participate in exercise > 3 days/wk
per week at a moderate or vigorous intensity pregnant or lactating women. Medications for
glycemic control (including insulin), β-blockers, glucocorticoids, testosterone, or other
medications for chronic pulmonary, cardiac or other systemic diseases.

Significant hypertension BP > 180 systolic or > 100 diastolic, at rest. Untreated
hypothyroidism or hyperthyroidism (will be included if treated and euthyroid) Active users
of tobacco and chronic alcohol abuse. Renal, hepatic, pulmonary, adrenal, or pituitary
disease. Liver function tests with > 2xULN.