OR40-6 Impaired B-Cell Secretory Capacity in Nonobese Compared to Obese Early Type 2 Diabetes and Healthy Controls

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR40-Type 2 Diabetes: Beta Cell Function and Novel Interventions
Clinical/Translational
Monday, June 23, 2014: 11:30 AM-1:00 PM
Presentation Start Time: 12:45 PM
W185 (McCormick Place West Building)
Lalitha Gudipaty, M.D., PhD1, Nora K Rosenfeld1, Carissa S. Fuller1, Marina Cuchel2 and Michael Roehrhoff Rickels, MD, MS1
1Hospital of the University of Pennsylvania, PA, 2University of Pennsylvania School of Medicine
The two main pathophysiologic abnormalities in Type 2 Diabetes (T2D) are impaired tissue sensitivity to insulin action (i.e. insulin resistance) and impaired pancreatic β-cell function.  While obesity plays a pivotal role in insulin resistance, this alone does not typically result in abnormal glucose tolerance and must be accompanied by a defect in β-cell insulin secretion.  We hypothesized that in nonobese T2D, insulin sensitivity may be normal but β-cell defects would predominant with impaired insulin synthesis and/or secretion compared to obese T2D.  As part of a study designed to investigate the role of incretin-based therapy vs. sulfonylurea therapy in early type 2 diabetes (T2D), we recruited T2D subjects with fasting glucose between 110-159 mg/dl off all anti-diabetic agents and measured β-cell function and secretory capacity using glucose-potentiated arginine (GPA) test during which acute insulin responses to arginine (5 g) were determined under fasting (AIRarg) and 230 mg/dl (AIRpot) and 340 mg/dl (AIRmax) hyperglycemic clamp conditions.  Subjects were classified as nonobese (BMI ≤ 28; N=12) or obese (BMI > 28; N=26) and compared with normal controls (N = 12) that were weight and race matched to the nonobese T2D subjects. 

Results: Analysis of baseline data revealed that while the nonobese and obese T2D subjects were similar in age, both groups were older than the normal control group (58.8 ± 2.5 vs. 54.5 ± 1.6 vs. 32.2 ± 2.5; P < 0.0001 for both vs. normal).  The acute insulin response to arginine was significantly lower in the nonobese T2D under 230 mg/dl hyperglycemic clamp conditions than the normal group (AIRpot 79.6 ± 15.5 vs. 136.9 ± 17.9 μU/mL; P <0.05).   Acute proinsulin responses to arginine (APRpot) were (APRpot: 17.9 ± 2.9 vs. 15.1 ± 1.0 vs. healthy 25.0 ± 2.7 pmol/L; P <0.01).  Fasting proinsulin:insulin ratios were greater by statistical trend across the groups (27.7 ± 5.2 vs. 20.8 ± 2.1 vs. 16.3 ± 2.9%; P <0.1).  Acute proinsulin/insulin ratios (PISR) to estimate the contents within the secretory granules of the β-cell reveal that nonobese T2D have a higher PISR than obese T2D subjects and healthy subjects under 230 mg/dl glucose conditions (4.7 ± 1.2 vs 2.2 ± 0.2 vs. 2.9 ± 0.3 %; P < 0.05).  Non-obese T2D subjects had decreased β-cell sensitivity to glucose compared to the normal controls (210 ± 20 vs. 193 ± 11 vs. 155 ± 8 mg/dl; P <0.05). Obese T2D subjects were insulin resistant (P < 0.001) while non-obese subjects had insulin sensitivity that was comparable to normal subjects. 

Conclusions: In nonobese T2D, β-cell defects predominate with impaired β-cell sensitivity to glucose and proinsulin processing compared to obese T2D and normal controls in the absence of insulin resistance.

Nothing to Disclose: LG, NKR, CSF, MC, MRR

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: This work was supported by the Pennsylvania Department of Health, Bureau of Health Statistics and Research (Penn Center for Excellence in Regenerative Medicine), Public Health Services Research Grants UL1TR000003 (University of Pennsylvania Clinical and Translational Research Center) and P30DK19525 (University of Pennsylvania Diabetes Research Center), the Peterman-Arnold Research Fellowship and the Welsh Fellowship (to L.G.), and the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity & Metabolism.
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