Mechanisms of Insulin Resistance in Man

PROJECT SUMMARY
Mechanisms of Insulin Resistance in Man
Almost ~ 100 million people in the US have type 2 diabetes (T2D) or pre-diabetes that accounts for 1 in 5
health care dollars. The prevalence of these metabolic disorders is increasing exponentially. Understanding the
pathogenesis of and developing better and rational therapies based on the causal factors for these conditions
is a very high priority. We have previously evaluated nighttime regulation of glucose and effects of counter-
regulatory hormones (glucagon, cortisol) on nocturnal endogenous glucose production (EGP) in T2D. We
observed that rates of EGP remained high all night (at 1AM vs. 4 AM vs. 7 AM) in T2D. However, we did not
determine whether the higher nighttime EGP was due to higher EGP rates all day i.e. post breakfast, post
lunch and post dinner. We also did not determine the daytime temporal profiles of EGP, insulin action and
secretion. Therefore, the mechanism of daytime regulation and diurnal pattern of EGP in T2D remains poorly
understood i.e. when do rates of EGP increase - are they higher throughout the day as they are during the
night; why is EGP higher – is it due to abnormalities in hepatic glycogen content? How can we control the
higher rates of EGP? We have designed a set of experiments to test hypotheses related to various specific
aims that address these fundamental questions. In Specific Aim 1A we will determine the diurnal pattern of
EGP using a stable label triple tracer approach and in Specific aim 1B concurrently estimate insulin action
and beta cell responsivity during the day in T2D. We will study the role of hepatic glycogen on nocturnal EGP
in T2D with glycogen loading vs. non-glycogen loading using NMR to measure hepatic glycogen content and
deuterium labeled water to measure gluconeogenesis as part of Specific Aim 2. We have designed a
mechanistic clinical trial in Specific Aim 3 to test the effects of modulators of gluconeogenesis (metformin),
glycogenolysis (insulin-glargine) and glucokinase activity (novel glucokinase activator drug: dorzagliatin) on
EGP in T2D. We have assembled a multi-disciplinary team of investigators (endocrinologists, mathematical
modelers, radiologist, biostatistician) to design the various specific aims in adult subjects with T2D using state
of the art imaging (NMRS of liver to estimate glycogen content), isotopic, glucose clamp techniques and
glucose/hormonal modeling coupled with CGM data for innovative and comprehensive assessments which will
be easily translatable to clinical practice. Taken together, we believe our approach will answer vital questions
regarding the regulation of daytime and nighttime glucose production on fasting and post-prandial
hyperglycemia in subjects with T2D. The planned research will fill knowledge gaps in regulation of
endogenous glucose production, glycogenolysis, and gluconeogenesis in people with T2D and provide insights
into future innovative therapies for this condition.

Grant Number: 5R01DK029953-42
NIH Institute/Center: NIH
Principal Investigator: RITA BASU