Elsevier

Endocrine Practice

Volume 21, Issue 12, December 2015, Pages 1344-1353
Endocrine Practice

Original Articles
Optimized 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

https://doi.org/10.4158/EP15898.ORGet rights and content

ABSTRACT

Objective: To assess β-cell function and insulin sensitivity following improvement in glycemic control in severely insulin-resistant patients with poorly controlled type 2 diabetes (T2D).

Methods: A subset of patients in a 24-week, open-label, randomized trial comparing thrice-daily (n = 14/162) versus twice-daily (n = 11/163) human regular U-500 insulin (U-500R) underwent mixed meal tolerance testing at baseline and endpoint. Baseline characteristics were similar between treatment groups (combined means: age, 54.0 years; diabetes duration, 13.6 years; body mass index, 38.8 kg/m2; glycated hemoglobin [HbA1c], 8.3%; U-100 insulin dose, 287.6 units/day, 2.6 units/kg/day). Primary outcome measure was ratio of area under the curve (AUC) for C-peptide to glucose (AUCC-peptide/AUCglucose) at 24-week endpoint.

Results: Change from baseline HbA1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. β-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUCC-peptide/AUCglucose increased 34.0% (ratio of least-squares geometric mean, 1.34; 95% confidence interval, 1.18 to 1.52; P = .0001). Integral of total insulin secretion rate increased from 27.0 to 33.7 nmol/m2, and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m2/mM (both, P = .02). Matsuda index improved from 0.8 to 1.3 (P = .008).

Conclusion: Despite long-standing diabetes and poor glycemic control at baseline, functional recovery of β-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.

Abbreviations:

AUC = area under the curve

BID = twice daily

HbA1c = glycated hemoglobin

ISR = insulin secretion rate

LSM = least-squares mean

MMTT = mixed meal tolerance test

PG = plasma glucose

T2D = type 2 diabetes

TDD = total daily dose

TID = thrice daily

U-500R = human regular U-500 insulin

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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