Recovery of acute insulin response (AIR) is shown to be associated with long-term outcomes of patients with early type 2 diabetes treated with short-term intensive insulin therapy (SIIT). However, the complexity of measuring an AIR limits its utility in a real-world clinical setting. The aim of the study was to assess fasting indicators that may estimate recovery of the AIR after SIIT. We enrolled 62 patients with type 2 diabetes mellitus (T2DM) of varying disease duration who had poor glycemic control. Participants were treated with SIIT using insulin pumps to achieve near normoglycemia for 7 days. The AIR before and after the therapy were measured by intravenous glucose tolerance tests. After the therapy, AIR increased from −16.7 (−117.4, 52.4) pmol/L·min to 178.7 (31.8, 390.7) pmol/L·min (
Type 2 diabetes mellitus (T2DM) is characterized by the persistent decline in
It is essential to repeatedly measure
We, therefore, conducted this prospective study by applying SIIT in patients with various T2DM duration. We analyzed the relationship between fasting parameters and AIR, in order to search for more convenient surrogates of AIR to facilitate the clinical application and monitoring strategy of SIIT.
Sixty-two patients, aged 20–75 years, who were diagnosed with T2DM according to WHO diagnostic criteria (1999) [
All patients were hospitalized throughout the study and guided to start lifestyle intervention. After the withdrawal of previous antihyperglycemic therapy for at least 24 hours, anthropometric indices were measured and blood samples for the FPG, HbA1c, fasting lipid profiles, fasting C peptide, and 2 h postprandial blood glucose were collected. An IVGTT was then conducted using 25 g of glucose (50 mL of 50% glucose solution) with serum samples obtained before and 1, 2, 4, 6, and 10 min after intravenous administration of glucose solution to measure insulin. The AIR was then calculated as the incremental trapezoidal area under the curve of insulin levels during IVGTT. After baseline assessment, all patients received SIIT using an insulin pump (Paradigm 712 pump, Medtronic Inc., Northridge, CA) with insulin lispro (Humalog®, Eli Lilly and Company, USA). The initial daily insulin dose was 0.5-0.6 U/kg and was divided into basal and premeal doses with a ratio of 50% : 50%. Dosages were titrated to achieve glycemic targets (fasting/premeal blood glucose 4.4~7.0 mmol/L and 2 h postprandial blood glucose (2hPG) 4.4–10 mmol/L) based on fingertip capillary blood glucose values which were measured seven times per day (before and 2 hours after three meals, at bedtime). After glycemic targets were achieved, treatment was maintained for additional 7 days and subsequently ceased after the last premeal dose (before supper) on the 7th day. No other hypoglycemic agents or lipid-lowering agents were added during SIIT. All baseline parameters were repeated after more than 10 hours postcessation of insulin infusion and an overnight fast.
HbA1c was measured by high-performance liquid chromatography (VARIANT II; Bio-Rad, Hercules, CA). Serum insulin was measured using chemiluminescence immunoassay (Access®, Beckman Coulter, California, USA). Total cholesterol and triglyceride were assayed by enzymatic colorimetric test. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured using direct enzymatic method. All assays were done in the central laboratory of the First Affiliated Hospital of Sun Yat-sen University.
The area under the curve of insulin was calculated by trapezoidal estimation. The AIR represented the incremental area above the baseline insulin level over the duration of 10 mins. Homeostasis model assessment was also applied for estimation of
Normally distributed variables were presented as mean ± standard deviation, and nonnormally distributed variables were presented as median (interquartile range). Patients were classified into two groups according to AIR after SIIT: group A, AIR after the therapy ≥ 300 pmol/L·min and group B, AIR after the therapy ≤ 300 pmol/L·min. This AIR value was chosen because, in one of our previous study, patients who experienced long-term remission had a mean posttreatment AIR of around 300 pmol/L·min [
The study population consisted of 36 men and 26 women, with a mean age of 55.9 ± 10.8 years. Median duration of diabetes was 3.0 years, and baseline HbA1c was 10.4 ± 1.9% (92.4 ± 20.0 mmol/mol). 17 (27.4%) of the participants were drug naïve, 12 (19.4%) were on oral hypoglycemic monotherapy, 26 (41.9%) were on combined oral hypoglycemic agents, and 7 (11.3%) were using insulin. The duration of insulin therapy, to achieve and maintain the predefined glycemic targets for seven days, was 12.0 ± 2.1 days. The median daily insulin dose on the first day achieving glycemic targets was 0.76 ± 0.32 U/kg. After SIIT, measures of hyperglycemia were markedly decreased: FPG (12.0 ± 3.0 mmol/L vs 7.7 ± 1.6 mmol/L,
Response to short-term intensive insulin therapy (SIIT) in all participants.
Overall | Group A ( |
Group B ( |
||
---|---|---|---|---|
Sex (male/female) | 36/26 | 12/7 | 24/19 | 0.78 |
Age (years) | 55.9 ± 10.8 | 57.3 ± 11.8 | 52.5 ± 7.1 | 0.05 |
Duration of diabetes (years) | 3.0 (0.2, 7.3) | 1.0 (0.2, 3.5) | 3.5(0.3, 9.0) | 0.10 |
Body mass index (kg/m2) | ||||
Before SIIT | 24.6 ± 3.0 | 25.7 ± 2.4 | 24.2 ± 3.1 | 0.69 |
After SIIT | 24.6 ± 3.0 | 25.4 ± 2.5 | 24.1 ± 3.1 | 0.12 |
Waist circumference (cm) | ||||
Before SIIT | 87.4 ± 8.8 | 90.8 ± 7.0 | 85.8 ± 9.2 | 0.04 |
After SIIT | 86.4 ± 8.3 |
88.9 ± 7.0 |
85.2 ± 8.7 | 0.11 |
Fasting plasma glucose (mmol/L) | ||||
Before SIIT | 12.0 ± 3.0 | 10.5 ± 2.2 | 12.7 ± 3.1 | 0.007 |
After SIIT | 7.7 ± 1.63 |
6.6 ± 1.1 |
8.2 ± 1.6 |
<0.001 |
Postprandial plasma glucose (mmol/L) | ||||
Before SIIT | 17.3 ± 5.2 | 16.1 ± 5.2 | 17.8 ± 5.2 | 0.25 |
After SIIT | 11.5 ± 3.7 |
9.2 ± 2.1 |
12.5 ± 3.8 |
0.001 |
HbA1c | ||||
Before SIIT (%) | 10.4 ± 1.9 | 9.9 ± 1.5 | 10.6 ± 2.0 | 0.22 |
(mmol/mol) | 92.4 ± 20.0 | 87.9 ± 16.5 | 94.6 ± 22.0 | |
After SIIT (%) | 9.3 ± 1.5 |
8.7 ± 1.2 |
9.5 ± 1.6 |
0.07 |
(mmol/mol) | 80.3 ± 16.5 |
74.1 ± 13.2 |
82.5 ± 17.6 | |
Uric acid ( | ||||
Before SIIT | 358.4 ± 91.7 | 400.7 ± 68.6 | 339.7 ± 95.2 | 0.15 |
After SIIT | 355.9 ± 78.3 | 383.7 ± 55.8 | 343.6 ± 84.0 | 0.03 |
Total cholesterol (mmol/L) | ||||
Before SIIT | 5.5 ± 1.2 | 5.3 ± 1.0 | 5.7 ± 1.3 | 0.27 |
After SIIT | 5.3 ± 1.2 | 5.0 ± 1.1 | 5.4 ± 1.2 | 0.23 |
Triglyceride (mmol/L) | ||||
Before SIIT | 2.0 ± 1.3 | 2.1 ± 1.5 | 1.9 ± 1.2 | 0.51 |
After SIIT | 1.5 ± 0.6 |
1.6 ± 0.5 | 1.5 ± 0.6 |
0.38 |
High-density lipoprotein cholesterol (mmol/L) | ||||
Before SIIT | 1.1 ± 0.2 | 1.0 ± 0.2 | 1.2 ± 0.3 | 0.15 |
After SIIT | 1.2 ± 0.2 |
1.00 ± 0.2 | 1.3 ± 0.3 |
<0.001 |
Low-density lipoprotein cholesterol (mmol/L) | ||||
Before SIIT | 3.8 ± 0.9 | 3.7 ± 0.7 | 3.8 ± 0.9 | 0.46 |
After SIIT | 3.5 ± 0.9 |
3.4 ± 0.8 | 3.6 ± 0.9 |
0.61 |
Alanine aminotransferase (U/L) | ||||
Before SIIT | 26.6 ± 14.3 | 28.3 ± 9.8 | 25.8 ± 15.9 | 0.53 |
After SIIT | 26.2 ± 17.2 | 25.5 ± 10.3 | 26. 6 ± 19.6 | 0.82 |
Aspartate aminotransferase (U/L) | ||||
Before SIIT | 22.7 ± 7.5 | 25.0 ± 7.2 | 21.7 ± 7.2 | 0.12 |
After SIIT | 24.7 ± 8.8 |
24.6 ± 7.0 | 24.8 ± 9.5 |
0.93 |
Fasting serum insulin (pmol/L) | ||||
Before SIIT | 48.0 ± 32.4 | 60.1 ± 31.8 | 43.2 ± 31.8 | 0.06 |
After SIIT | 39.0 ± 27.6 |
44.9 ± 28.2 |
36.6 ± 27.6 |
0.27 |
Fasting C peptide (nmol/L) | ||||
Before SIIT | 0.8 ± 0.3 | 1.0 ± 0.3 | 0.7 ± 0.3 | 0.001 |
After SIIT | 0.7 ± 0.2 |
0. 8 ± 0.2 |
0.6 ± 0.2 |
0.01 |
HOMA-B | ||||
Before SIIT | 18.7 (9.6, 24.2) | 24.5 (16.1, 36.3) | 15.5 (6.7, 23.8) | 0.002 |
After SIIT | 28.5 (18.6, 42.7) |
49.9 (32.8, 64.9) |
22.0 (16. 2, 32.7) |
<0.001 |
HOMA-IR | ||||
Before SIIT | 3.4 (2.2, 5.5) | 4.7 (2.4, 6.7) | 3.1 (2.1, 4.8) | 0.18 |
After SIIT | 1.7 (1.2, 2.6) |
1.8 (1.4, 2.4) |
1.6 (1.2, 3.0) |
0.77 |
Acute insulin response (pmol/L·min) | ||||
Before SIIT | −16.7 (−117.4, 52.4) | 16.7 ± 202.8 | −23.4 ± 129.0 | 0.35 |
After SIIT | 178.7 (31.8, 390.7) |
480.0 (395.4, 725.4) |
69.4 (5.7, 188.7) |
<0.001 |
△AIR | 264.5 ± 332.6 | 600.0 ± 390.6 | 116.0 ± 147.0 | <0.001 |
Group A: participants with acute insulin response (AIR) after SIIT ≥ 300 pmol/L·min. Group B: participants with AIR after SIIT < 300 pmol/L·min.
Recovery of the acute insulin response (AIR) after short-term intensive insulin therapy. The AIR significantly improved after the treatment (
At baseline, participants with better AIR after therapy (group A) were younger in age, had a higher waist circumference, lower FPG, higher fasting C peptide levels, and higher HOMA-B. After SIIT, group A had significantly lower FPG, 2hPG, HbA1c, and HDL-C levels and higher fasting C peptide levels, HOMA-B, and AIR compared with group B (Table
To investigate the association between FPG and AIR, data before and after SIIT were pooled and plotted together. As shown in Figure
The close association between fasting plasma glucose (FPG) and acute insulin response (AIR). (a) AIR disappeared when FPG > 10 mmol/L, and it was negatively associated with FPG when FPG < 0 mmol/L. (b) FPG after SIIT was negatively correlated with ∆AIR. Performance of the estimating formulae was illustrated by comparing estimated AIR (eAIR) with actual AIR (c), as well as estimated ∆AIR (e∆AIR) with actual ∆AIR, respectively, in patients with FPG < 10 mmol/L after SIIT (
Independent predictors of AIR recovery were explored using stepwise logistic regression models, with AIR after the therapy ≥ 300 pmol/L·min as the dependent variable. Variables with a
Stepwise logistic regression analysis of AIR after SIIT ≥ 300 pmol/L·min (dependent variable).
OR | 95% CI | CoxSnell | ||
---|---|---|---|---|
Unadjusted model | 0.47 | |||
FPG after SIIT (per mg/dL) | 0.93 | 0.89–0.98 | 0.002 | |
HDL-C after SIIT (per mg/dL) | 0.83 | 0.71–0.97 | 0.02 | |
Baseline fasting C peptide (per ng/mL) | 3.70 | 1.22–11.20 | 0.02 | |
Adjusted model | ||||
Age (>55 years) | 0.41 | 0.05–3.04 | 0.38 | 0.50 |
Disease duration (>3 years) | 0.44 | 0.07–2.69 | 0.38 | |
Baseline BMI (>25 kg/m2) | 0.33 | 0.04–2.74 | 0.30 | |
FPG after SIIT (per mg/dL) | 0.92 | 0.87–0.98 | 0.02 | |
HDL-C after SIIT (per mg/dL) | 0.79 | 0.65–0.96 | 0.006 | |
Baseline fasting C peptide (per ng/mL) | 4.67 | 1.21–18.02 | 0.03 |
FPG: fasting plasma glucose; BMI: body mass index; HDL-C: high-density lipoprotein cholesterol.
We further developed formulae using multiple linear regression analyses in order to estimate AIR after SIIT and △AIR. As AIR was negligible if FPG exceeded 10 mmol/L (Figure
Multiple linear regression analysis for acute insulin response (AIR) after SIIT and change of AIR (△AIR).
Standardized |
|||||
---|---|---|---|---|---|
Constant | 925.2 | ||||
FPG after SIIT (mmol/L) | −138.0 | −0.53 | <0.001 | 0.42 | 0.39 |
Baseline fasting C peptide (nmol/L) | 447.6 | 0.40 | 0.001 | ||
△ | |||||
Constant | 1380.0 | ||||
FPG after SIIT (mmol/L) | −136.8 | −0.50 | <0.001 | ||
Baseline fasting C peptide (nmol/L) | 401.4 | 0.35 | 0.002 | 0.50 | 0.47 |
HDL-C after SIIT (mmol/L) | −357.6 | −0.25 | 0.025 |
FPG: fasting plasma glucose; HDL-C: high-density lipoprotein cholesterol.
The predictive capacity of the formula was fairly good, as both the estimated eAIR and e△AIR correlated well with and were close to their respective actual values (276.8 ± 218.8 vs 280.0 ± 327.2 pmol/L
As expected, in this study, we demonstrated that first-phase insulin secretion was partially restored after normalizing blood glucose with SIIT in patients of varying diabetes duration. There was a robust association between posttherapy FPG and the recovery of AIR. More importantly, the improvement of AIR could be conveniently estimated using FPG and other fasting parameters, with acceptable accuracy.
AIR, which represents first-phase insulin secretion, is characterized by rapid insulin secretion shortly after (within 10 minutes) prompt elevation of blood glucose levels. Thus, AIR can significantly impact hepatic glucose output and postprandial plasma glucose excursions [
The recovery of AIR by intensive insulin therapy has been reported in various studies over the last two decades [
There is a lack of consensus on the optimal duration of insulin therapy. In previous studies, the therapy, which usually required inpatient monitoring, lasted in varying periods, from 2 weeks to several months [
Another major finding in this study is the close relationship between the recovery of AIR and simple fasting serum parameters, in particular, FPG post-SIIT. The FPG is a direct reflection of glycemic homeostasis in the basal state. Elevations of FPG from the normal range to diabetic threshold are associated with a progressive decline in
Findings in this study also indicate the potential feasibility of a new monitoring strategy for reversibility of
In this study, other parameters of
In conclusion, optimal glycemic control for only one week by SIIT was sufficient to induce prominent recovery of AIR in patients of varying disease duration of T2DM and this response can be predicted and estimated using FPG after SIIT and other simple indicators. While these findings require further validation in a larger population with more diverse baseline characteristics, these discoveries may potentially result in the renewal of current practice and the development of monitoring strategies for SIIT.
The data used to support the findings of this study are available from the corresponding author upon request.
This work was presented as a poster in the 78th Scientific Sessions of American Diabetes Association.
The authors declare that they have no competing interests.
Liehua Liu conducted the study, analyzed the data, and wrote the manuscript. Siyue Yang conducted the study and helped in writing the manuscript. Liehua Liu and Siyue Yang contributed equally to this manuscript. Jianbin Liu contributed to data collection and preparation of manuscript. Hai Li helped with data collection. Juan Liu, Xiaopei Cao, and Haipeng Xiao contributed to data analysis. Yanbing Li designed the study, analyzed the data, and reviewed the manuscript. All authors read and approved the final version of the manuscript.
This study is funded by the National Key R&D Program of China (2018YFC1314100); 5010 Project of Sun Yat-sen University (no. 2010002); Industrial Technology Research and Development funding projects, Guangdong Science and Technology Department (no. 2012A030400006); Guangzhou Science and Technology Program key projects, China (no. 2014Y2-00127); Doctoral Fund of Ministry of Education, China (no. 20130171110067); funding of Key Medical Laboratory of Guangdong Province; and Funding of National Key Clinical Discipline, China. We thank Dr. Jason Ha from Monash University, Australia, for his assistance in revising the manuscript.