Original ArticlesOptimized Human Regular U-500 Insulin Treatment Improves β-Cell Function in Severely Insulin-Resistant Patients with Long-Standing Type 2 Diabetes and High Insulin Requirements
Section snippets
INTRODUCTION
Deterioration of pancreatic β-cell function and insulin resistance are key pathophysiologic mechanisms in the development and progression of type 2 diabetes (T2D) (1). Although normal β-cells have the capacity to keep glucose fluctuations in a relatively narrow range in the presence of reduced insulin sensitivity, chronic hyperglycemia (i.e., glucotoxicity) alone or coupled with elevated plasma free fatty acid levels (i.e., glucolipotoxicity) may contribute to β-cell dysfunction,
METHODS
A subgroup of patients from a 24-week, phase 4, open-label, randomized, 2-arm, parallel, multicenter, clinical trial conducted between February 2013 and May 2014 in the United States and Puerto Rico (13), were randomly assigned to participate in a mixed meal tolerance test (MMTT) substudy. Patients enrolled were 18 to 75 years of age with inadequately controlled T2D (glycated hemoglobin [HbA1c], 7.5 to 12.0%) treated with high-dose U-100 insulin (201 to 600 units/day) for at least 3
Patient Disposition and Baseline Characteristics
Twenty-five (TID, n = 14; BID, n = 11) of the 325 patients who were randomized to either the TID (n = 162) or BID (n = 163) treatment group in the primary study (13) were enrolled into the MMTT substudy. Twenty-four patients completed each MMTT as stated in the protocol. One patient inadvertently took their morning dose of U-500R just before the MMTT at week 24, and, accordingly, those data were excluded from analysis. Baseline characteristics were similar between the TID and BID treatment
DISCUSSION
This study is the first to assess β-cell function and insulin sensitivity associated with the use of high-dose concentrated U-500R in a unique cohort of severely insulin-resistant patients with inadequate glycemic control and high insulin requirements at baseline and with a long history of T2D. The magnitude of improvement in β-cell function, particularly the observed absolute increase in integral of total ISR, was remarkable, especially in light of lower PG and AUCglucose at endpoint and the
CONCLUSION
Functional recovery of β-cells does occur in conjunction with improved glycemic control in severely insulin-resistant and overweight/obese patients with uncontrolled and long-standing T2D. These findings may have important clinical implications and call for further investigative study of β-cell function and insulin action in this specific subpopulation of T2D.
DISCLOSURE
A.M. has consulted for Eli Lilly and Company, Boehringer Ingelheim, and Poxel and has provided research support to Boehringer Ingelheim and Poxel. J.R. has served on the scientific advisory boards of and has received honoraria or consulting fees from Sanofi, Novo Nordisk, Eli Lilly and Company, GlaxoSmithKline, Takeda, Merck, Daiichi Sankyo, Janssen, Novartis, Boehringer Ingelheim, MannKind, Halozyme, Intarcia, and Lexicon and has received grants from or provided research support to Merck,
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