Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. Efforts continue to investigate factors which affect insulin action and secretion. We have also investigated the portion of glucose uptake that is non-insulin mediated. Using a large dataset, we were able to reproduce previous estimates of rates of non-insulin mediated glucose uptake (NIMGU). We also found that NIMGU was positively related to adiposity, and that it increased with worsening glucose tolerance. We also investigated parental effects on risk factors for diabetes. We found that offspring of fathers with early onset (<35 years of age) have less body fat and lower insulin secretion, despite similar measures of insulin action. These data indicate a paternal imprinted effect in these individuals. We are continuing to investigate additional factors which control insulin secretion and insulin action. Individuals who are undergoing bariatric surgery using the following techniques: Roux-en-Y gastric bypass, laporoscopic band, or gastric sleeve will undergo measures of insulin action, insulin secretion and meal tests prior to and one month following the surgery. This study will investigate how by-pass of the duodenum and specific areas of the stomach influence insulin action and secretion as well as their affect on gastrointestinal hormones. Adiposity is also a pro-inflammatory state and such inflammation may affect insulin action directly. We have previously investigated the role of recently identified adipose tissue macrophages and their associations with obesity and insulin action. Adipose tissue macrophages increased with adiposity, and were negatively associated with insulin action, although not independent of adiposity. However, markers of macrophage activation in adipose tissue (specifically plasminogen activator inhibitor-1 (PAI-1) were associated worsening insulin action independent of body fat, indicating a role for macrophage activation in insulin resistance. Previous predictors of weight gain based on this study have included, higher respiratory quotient, higher insulin mediated glucose uptake, lower free T3, and relatively lower energy expenditure. Variance in adiposity within the Pima Indian population is largely due to genetic varation as well. Melanocortin 4 receptor variants are the most common monogenetic cause of obesity. Functional melanocortin 4 receptor variants have been identified in the Pima Indian population, including a novel variant predicting a STOP codon. These variants are associated with increased adiposity, but also with lower energy expenditure. This is the first demonstration of an association between a monogenic form of obesity and lower metabolic rate in humans. We have also identified that markers of inflammation, including white blood cell count but also importantly adipose tissue markers are negatively associated with energy expenditure. This indicates that the increasing inflammation seen with increased adiposity may also serve as a brake to further weight gain.

Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2010
Total Cost
$160,133
Indirect Cost
City
State
Country
Zip Code
Heinitz, Sascha; Basolo, Alessio; Piomelli, Daniele et al. (2018) Endocannabinoid Anandamide Mediates the Effect of Skeletal Muscle Sphingomyelins on Human Energy Expenditure. J Clin Endocrinol Metab :
Piaggi, P; Vinales, K L; Basolo, A et al. (2018) Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms. J Endocrinol Invest 41:83-89
Heinitz, Sascha; Piaggi, Paolo; Bogardus, Clifton et al. (2018) Decline in the acute insulin response in relationship to plasma glucose concentrations. Diabetes Metab Res Rev 34:
Paddock, Ethan; Looker, Helen C; Piaggi, Paolo et al. (2018) One-Hour Plasma Glucose Compared With Two-Hour Plasma Glucose in Relation to Diabetic Retinopathy in American Indians. Diabetes Care 41:1212-1217
Heinitz, Sascha; Basolo, Alessio; Piaggi, Paolo et al. (2018) Peripheral Endocannabinoids Associated With Energy Expenditure in Native Americans of Southwestern Heritage. J Clin Endocrinol Metab 103:1077-1087
Piaggi, Paolo; Masindova, Ivica; Muller, Yunhua L et al. (2017) A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated With Reduced Energy Expenditure in American Indians. Diabetes 66:2284-2295
Chang, Douglas C; Piaggi, Paolo; Krakoff, Jonathan (2017) A Novel Approach to Predict 24-Hour Energy Expenditure Based on Hematologic Volumes: Development and Validation of Models Comparable to Mifflin-St Jeor and Body Composition Models. J Acad Nutr Diet 117:1177-1187
Frankl, Joseph; Piaggi, Paolo; Foley, James E et al. (2017) In Vitro lipolysis is associated with whole-body lipid oxidation and weight gain in humans. Obesity (Silver Spring) 25:207-214
Chang, Douglas C; Piaggi, Paolo; Hanson, Robert L et al. (2017) Autoantibodies against PFDN2 are associated with an increased risk of type 2 diabetes: A case-control study. Diabetes Metab Res Rev :
Heinitz, S; Piaggi, P; Vinales, K L et al. (2017) Specific skeletal muscle sphingolipid compounds in energy expenditure regulation and weight gain in Native Americans of Southwestern heritage. Int J Obes (Lond) 41:1585-1593

Showing the most recent 10 out of 42 publications