Ling W, Wang YC, Huang Y, Ou YF, Jiang YC. Islet β-cell function preservation by different anti-diabetic treatments in Chinese elderly patients with type 2 diabetes mellitus. World J Diabetes 2025; 16(2): 94976 [DOI: 10.4239/wjd.v16.i2.94976]
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Wei Ling, Department of Science Laboratory, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541002, Guangxi Zhuang Autonomous Region, China
Yan-Chao Wang, Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin 541100, Guangxi Zhuang Autonomous Region, China
Yi Huang, Faculty of Basic Medicine, Guilin Medical University, Guilin 541100, Guangxi Zhuang Autonomous Region, China
Yang-Fu Ou, Department of Geriatrics, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
Yan-Chun Jiang, Department of Neurology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541002, Guangxi Zhuang Autonomous Region, China
Author contributions: Ling W design the study and draft the manuscript; Wang YC and Huang Y collect and generate the raw data; Ou YF and Jiang YC assembled and analyzed and/or interpretated the data; all authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of the Nanxishan Hospital of Guangxi Zhuang Autonomous Region (Approval No. NXSYY-2024-209).
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors have declared that no conflict of interests exists.
Data sharing statement: The raw data are available upon reasonable request from the corresponding author at lingwei19901016@163.com.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Received: March 29, 2024 Revised: September 7, 2024 Accepted: December 3, 2024 Published online: February 15, 2025 Processing time: 276 Days and 7 Hours
Abstract
BACKGROUND
The preservation of islet β-cell function in elderly patients with type 2 diabetes mellitus (T2DM) is a top priority for diabetic control.
AIM
To assess the preservation of islet β-cell function among elderly Chinese patients with T2DM after different anti-diabetic treatments.
METHODS
In this longitudinal observational study, elderly patients with T2DM treated with insulin, oral antidiabetic drugs or a combination of both were enrolled to disclose their islet β-cell function between baseline and follow-up. Islet β-cell function was determined by the plasma Homeostasis Model for β-cell function (HOMA-β), C-peptide and area under the curve (AUC) based on oral glucose tolerance test. Changes in β-cell function (decrement or increment from baseline) between different therapy groups were the outcomes.
RESULTS
In total, 745 elderly patients (≥ 60 years) with T2DM [insulin monotherapy, n = 105; oral anti-diabetic drugs (OAD) monotherapy, n = 321; insulin plus OAD, n = 319] had their baseline and follow-up β-cell function assessed during a median observation period of 4.5 years (range, 3.0-7.2 years). Overall, islet β-cell function (HOMA-β, fasting C-peptide, fasting insulin, AUCc-pep, AUCins, AUCc-pep/AUCglu, AUCins/AUCglu) consistently deteriorated over time regardless of the three different antidiabetic treatments. No statistical differences in decrement were observed among the three groups regarding the islet β-cell function indices. All three groups showed an increased ratio of delayed insulin secretion response after 4.5 years of observation.
CONCLUSION
In Chinese elderly patients with T2DM, islet β-cell function progressively declines regardless of insulin supplement or insulin plus OAD treatments.
Core Tip: In this longitudinal observational study, elderly type 2 diabetic patients receiving insulin, oral hypoglycemic drugs, or combination therapy were included to disclose their baseline and follow-up β-cell function. Results showed that islet β-cell function progressively decline regardless of any insulin supplement or oral antidiabetic treatments in Chinese elderly patients with type 2 diabetes.
Citation: Ling W, Wang YC, Huang Y, Ou YF, Jiang YC. Islet β-cell function preservation by different anti-diabetic treatments in Chinese elderly patients with type 2 diabetes mellitus. World J Diabetes 2025; 16(2): 94976
The preservation of islet β-cell function in patients with type 2 diabetes mellitus (T2DM) remains a top priority for glycemic control. The United Kingdom Prospective Diabetes Study (UKPDS) has clearly shown that islet β-cell function deteriorates over time irrespective of any glucose-lowering modalities, including exogenous insulin[1-3]. Whereas results from more recent studies, including the one by Weng et al[4] showed that short-term exogenous insulin intervention has favorable outcomes in the maintenance of β-cell function and remission of hyperglycemia in adult patients with T2DM[5,6]. Recently, the Restoring Insulin Secretion (RISE) Adult Medication Study has disclosed that early intervention with insulin glargine was not associated with any improvement in β-cell function in youth with impaired glucose tolerance (IGT) or early diagnosed T2DM[7]. Furthermore, the RISE Pediatric Medication Study also revealed that all β-cell measures at 12 months and 15 months were worse than baseline in youth with IGT or recently diagnosed T2DM[8]. These conflicting findings might have affected the clinical choices of treatment modalities, and the preservation of islet β-cell function in patients with T2DM remains an important issue to address.
The reasons for these controversial opinions remain unclear, yet age may play a crucial role regarding the declining trend of β-cell function. Notably, across the spectrum of patients with T2DM, older adults have the highest prevalence[9]. More than 25% of adults aged > 65 years in the United States have diabetes[10]. Elderly patients with T2DM have a higher risk of diabetic complications and pose a heavier burden on healthcare systems and social economics[11,12]. However, no studies have yet evaluated the effect of different anti-diabetic therapies on β-cell function in an exclusively elderly population. Considering that most patients with T2DM are older adults and that T2DM in the Asia older individuals represents a more severe and rapidly progressive condition than Caucasian patients with diabetes, it is of particular importance to better understand the effect of different anti-diabetic therapies on islet β-cell function in these populations. This study aims to scrutinize the changes in β-cell function in Chinese elderly patients with T2DM after different anti-diabetic therapies.
MATERIALS AND METHODS
Participants
This study included clinically diagnosed patients with T2DM aged ≥ 60 years from the Nanxishan Hospital of Guangxi Zhuang Autonomous Region and the Affiliated Hospital of Guilin Medical University. All newly diagnosed patients were naïve to any anti-hyperglycemia therapy, while the previously diagnosed patients had been treated with glucose-lowering regimens, including exogenous insulin, oral anti-diabetic drugs (OAD), or a combination of both. Patients were included if they were patients with T2DM aged ≥ 60 years. Patients with type 1 diabetes mellitus, acute or severe chronic diabetic complications, critical illnesses, or malignancies were excluded. Patients diagnosed with T2DM secondary to other diseases, such as Cushing’s syndrome or pancreatic diseases, were also excluded. This study was approved by the Research Ethics Board of Nanxishan Hospital of Guangxi Zhuang Autonomous Region. Written informed consent was obtained from all participants before the treatment.
Study design
This was a longitudinal study conducted between 2009 and 2017. Patients were treated with standard glucose-lowering regimens to reach fasting glucose between 6.5 mmol/L and 7.5 mmol/L using exogenous insulin, OAD, or a combination by diabetologists, according to the guidelines. Based on their prescriptions, the patients were divided into three groups: (1) Insulin monotherapy; (2) OAD monotherapy; and (3) Combined therapy (insulin plus OAD). Islet β-cell function was compared between before and after treatment in each group. For patients who received OAD monotherapy, those with a body mass index (BMI) level of < 25 kg/m2 were initially treated with sulfonylurea drugs, acarbose, pioglitazone or DPP-4 inhibitors, whereas those with a BMI > 25 kg/m2 were initially treated with metformin. Patients were initially treated with a single OAD, and a combination of different OADs was administered in patients who could not maintain euglycemia. Patients who received insulin monotherapy were administered pre-meal insulin aspart or insulin detemir at bedtime using multiple daily insulin injections. The doses of insulin or OAD were prescribed by our diabetologists based on the patients’ glucose levels and body weight. If the treatments with monotherapy still failed to achieve the target glucose level (fasting glucose between 6.5 mmol/L to 7.5 mmol/L), the OAD or exogenous insulin would be added subsequently. All patients received diabetes education and were instructed to perform adequate exercise and maintain a healthy diet. During the observation period, patients were instructed to monitor their glucose levels daily at home. All patients were provided with access to a diabetologist at any time for consultation.
Islet β-cell function indices and other laboratory measurements
A standard questionnaire was administered by trained staff to record patients’ demographic and clinical data. After fasting overnight for 10 hours, venous blood samples were collected to measure fasting plasma glucose, fasting C-peptide, fasting insulin, HbA1c, lipid profiles, plasma creatinine, and plasma urea levels. Blood samples were also drawn at 0, 30, 60, 120, and 180 minutes after a 75 g glucose load to measure glucose, C-peptide, and insulin levels in all participants. All hospitalized patients with T2DM routinely underwent an oral glucose tolerance test (OGTT) to evaluate their β-cell function before any treatment. Before the OGTT, hypoglycemic treatments were withheld for 24 hours to wash out drug effects. Islet β-cell function was determined by plasma C-peptide, plasma insulin, calculated insulin and C-peptide area under the curve (AUCins and AUCc-pep), AUCc-pep/AUCglu and AUCins/AUCglu based on the OGTT values by the trapezoidal rule. The early phase of insulin secretion function was reflected by the C-peptide index (ΔC30/ΔG30), and the ratio of delayed insulin response was compared before and after treatment. Islet β-cell function, insulin resistance and insulin sensitivity were also measured by Homeostasis Model for β-cell function [HOMA-β = 20 × fasting insulin/(fasting glucose – 3.5)], Homeostasis Model for Insulin Resistance (HOMA-IR) = fasting glucose × fasting insulin/22.5 and Matsuda index = 10000/(mean glucose × mean insulin × fasting glucose × fasting insulin)0.5, respectively.
Statistical analyses
Statistical analyses were performed using the SPSS 25.0 software (IBM Corporation, Armonk, NY, United States). Baseline covariates were balanced by the method of propensity score-matching using MatchIt v 3.0.2 (http://gking.harvard.edu/matchit). The paired t-test or Wilcoxon matched paired test was used to assess differences in variables before and after the intervention. χ2 tests were performed to analyze categorical variables. Group comparisons were conducted using a one-way analysis of variance (ANOVA) with a t-test or Kruskal-Waillis test. Significance was defined as a two-tailed P < 0.05.
RESULTS
Participants’ characteristics
A total of 745 elderly patients with T2DM (mean age: 68.8 ± 5.8 years; men: 45.0%) who had baseline and follow-up β-cell function assessments were included in this study. All the participants were of Asian descent, comprising 555 Han individuals, 145 Zhuang individuals, and 45 individuals from other minority groups. The mean follow-up duration was 4.5 years (1-7.2 years). Among these, 37.7% were newly diagnosed, whereas 62.3% were previously diagnosed (mean disease duration: 3.2 years). Table 1 and Table 2 shows the pre-matched and post-matched demographic and metabolic characteristics of patients receiving insulin monotherapy (pre: n = 105; post: n = 88), OAD monotherapy (pre: n = 321; post: n = 189), and combined therapy (pre: n = 319; post: n = 189). Overall, the OAD group had significantly lower diastolic blood pressure, plasma urea and creatinine, fasting glucose, postprandial glucose, and HbA1c, while higher levels of triglycerides, fasting insulin, fasting C-peptide, and HOMA-β. Significant differences were observed in other baseline measurements among the three groups.
Table 1 Clinical characteristics of included participants before propensity score matching.
Insulin
OAD
Insulin + OAD
P value
Patients (n)
105
321
319
-
Men, n (%)
47 (44.8)
164 (51.1)
142 (44.5)
0.365
Age (year)
67.2 ± 5.8
69.3 ± 5.8
68.1 ± 5.8
0.269
BMI (kg/m2)
24.4 ± 3.3
24.4 ± 3.3
25.6 ± 3.8
0.289
Weight
65.9 ± 6.6
65.1 ± 7.5
68.3 ± 6.7
0.189
Waist (cm)
85.8 ± 9.7
85.7 ± 10.4
89.6 ± 10.6
0.176
SBP (mmHg)
150.1 ± 21.8
141 ± 23.3
143.2 ± 21.8
0.021
DBP (mmHg)
81.2 ± 12.5
75.6 ± 12.1
75.9 ± 12.3
0.012
Hypertension (%)
70.1
49.1
68.1
0.027
HbA1c (%)
8.6 ± 2.8
7.8 ± 2.3
9.6 ± 2.6
0.018
HDL-C (mmol/L)
1.27 ± 0.4
1.24 ± 0.35
1.23 ± 0.33
0.738
LDL-C (mmol/L)
3.72 ± 1.19
3.57 ± 0.97
3.42 ± 0.9
0.515
Total cholesterol (mmol/L)
5.7 ± 1.38
5.59 ± 1.17
5.4 ± 1.1
0.525
Triglycerides (mmol/L)
1.64 ± 1.01
1.83 ± 1.48
1.67 ± 1.01
0.018
Plasma creatinine (μmol/L)
178.43 ± 114.27
142.24 ± 88.74
265.87 ± 167.94
< 0.001
Plasma urea (mmol/L)
6.0 ± 3.8
5.7 ± 3.2
6.4 ± 3.9
0.013
eGFR [mL/(min·1.73m2)]
84.4 ± 15.2
99.5 ± 16.3
77.1 ± 17.5
0.011
Fasting glucose (mmol/L)
8.34 ± 2.69
6.91 ± 2.9
9.1 ± 4.3
0.023
Fasting insulin (pmol/L)
51.2 (30.3-91.9)
55.6 (30.5-92.7)
53.3 (23.1-93.0)
0.712
Fasting c peptide (nmol/L)
0.64 (0.46-1.0)
0.8 (0.5-1.12)
0.58 (0.4-0.88)
0.002
Postprandial glucose (mmol/L)
11.8 ± 4.9
12.2 ± 4.5
13.6 ± 5.3
0.019
Postprandial insulin (pmol/L)
152.6 (70.2-305)
184.5 (90.2-351.9)
128.3 (68.4-318.9)
0.036
Postprandial c peptide (nmol/L)
1.48 (0.78-1.89)
1.79 (1.18-2.59)
1.2 (0.68-1.78)
< 0.001
Log HOMA-β
5.48 ± 0.17
5.98 ± 0.08
5.49 ± 0.08
0.019
Log HOMA-IR
2.66 ± 0.13
2.78 ± 0.08
2.76 ± 0.07
0.625
Diabetic nephrology, n (%)
20 (19.0)
99 (30.8)
102 (31.9)
Diabetic retinopathy, n (%)
15 (14.2)
45 (14.0)
77 (24.1)
Diabetic neuropathy, n (%)
25 (23.8)
71 (22.1)
82 (25.7)
Any diabetic vascular disease, n (%)
35 (33.3)
156 (48.6)
150 (47.0)
Table 2 Clinical characteristics of included participants after propensity score matching.
OAD vs insulin
OAD vs insulin + OAD
Insulin vs insulin + OAD
Insulin
OAD
P value
Insulin
Insulin + OAD
P value
OAD
Insulin + OAD
P value
Patients (n)
96
96
189
189
88
88
Men, n (%)
44 (45.8)
46 (47.9)
0.772
79 (41.7)
74 (39.1)
0.601
37 (42.0)
41 (46.5)
0.544
Age (year)
58.3 ± 4.8
57.3 ± 5.5
0.484
60.2 ± 13.4
59.1 ± 12.8
0.755
58.1 ± 4.8
59.3 ± 4.4
0.526
BMI (kg/m2)
23.4 ± 2.3
23.0 ± 3.3
0.448
24.6 ± 4.6
25.1 ±4.2
0.788
24.2 ± 3.5
24.9 ± 3.6
0.852
Weight
65.1 ± 7.5
65.9 ± 6.6
0.596
65.3 ± 6.7
64.8 ± 6.6
0.458
68.3 ± 6.7
65.1 ± 7.5
0.336
Waist (cm)
84.7 ± 11.4
85.2 ± 10.7
0.234
86.6 ± 9.6
87.4 ± 10.7
0.635
88.6 ± 11.6
89.7 ± 10.5
0.452
SBP (mmHg)
140 ± 22.3
138.1 ± 22.8
0.288
137.3 ± 24.1
139.1 ± 20.2
0.189
140.2 ± 23.2
139 ± 19.3
0.793
DBP (mmHg)
81.6 ± 12.1
81.2 ± 11.5
0.938
78.5 ± 12.5
79.2 ± 11.2
0.171
81.9 ± 12.3
81.6 ± 10.1
0.549
Hypertension (%)
43.7
36.4
0.501
39.7
40.7
0.842
42
39.8
0.891
HbA1c (%)
8.9± 2.3
8.6 ± 2.2
0.238
9.40 ± 2.19
9.43 ± 2.3
0.869
9.4 ± 3.9
9.6 ± 3.5
0.384
HDL-C (mmol/L)
1.34 ± 0.51
1.37 ± 0.43
0.663
1.25 ± 0.36
1.25 ± 0.46
0.325
1.33 ± 0.75
1.31 ± 0.66
0.874
LDL-C (mmol/L)
3.47 ± 0.88
3.42 ± 1.09
0.236
3.62 ± 0.99
3.832 ± 1.19
0.331
3.44 ± 1.15
3.67 ± 1.36
0.589
Total cholesterol (mmol/L)
5.44 ± 1.08
5.41 ± 1.42
0.132
5.66 ± 1.21
5.71 ± 1.39
0.265
5.51 ± 1.06
5.69 ± 1.09
0.874
Triglycerides (mmol/L)
1.63 ± 1.33
1.69 ± 1.21
0.785
1.88 ± 1.11
1.89 ± 1.25
0.836
1.77 ± 1.36
1.98 ± 1.48
0.458
Plasma creatinine (μmol/L)
136.24 ± 87.6
148.43 ± 110.6
0.321
185.87 ± 95.4
198.43 ± 104.3
0.451
165.87 ± 76.6
162.24 ± 88.6
0.541
Plasma urea (mmol/L)
5.61 ± 1.3
5.66 ± 1.8
0.654
6.53 ± 1.9
6.36 ± 1.7
0.546
5.89 ± 2.0
6.32 ± 2.6
0.359
eGFR [mL/(min·1.73m2)]
101.5 ± 12.4
97.4 ± 13.6
0.213
84.5 ± 18.6
75.1 ± 17.6
0.336
88.4 ± 15.5
78.1 ± 16.4
0.125
Fasting glucose (mmol/L)
7.97 ± 2.13
7.89 ± 2.47
0.365
8.56 ± 3.02
8.61 ± 3.00
0.836
8.64 ± 2.15
9.27 ± 3.13
0.381
Fasting insulin (pmol/L)
60.6 (36.5-65.7)
57.2 (29.3-75.9)
0.817
59.3 (33.1-69.0)
65.2 (36.3-69.9)
0.938
60.3 (31-68)
66.6 (29.5-68.7)
0.918
Fasting c peptide (nmol/L)
0.73 (0.54-0.86)
0.77 (0.50-1.07)
0.544
0.72 (0.50-0.90)
0.68 (0.47-0.88)
0.541
0.73 (0.51-0.85)
0.67 (0.45-0.79)
0.496
Postprandial glucose (mmol/L)
12.3 ± 4.7
12.2 ± 4.1
0.847
13.3 ± 5.3
13.3 ± 4.9
0.981
13.6 ± 5.3
14.0 ± 4.5
0.977
Postprandial insulin (pmol/L)
232.5 (123.2-232.9)
232.6 (131.2-254)
0.501
222.3 (111-238.9)
222.6 (97.2-225)
0.403
194.3 (121.4-194.9)
194.5 (66.2-194.9)
0.411
Postprandial c peptide (nmol/L)
1.79 (0.98-0.91)
1.69 (1.11-2.38)
0.298
1.62 (1.03-1.93)
1.43 (0.82-1.81)
0.089
1.41 (0.86-1.71)
1.36 (0.75-1.87)
0.58
Log HOMA-β
5.60 ± 77
5.57 ± 0.91
0.864
5.41 ± 0.86
5.43 ± 0.84
0.991
5.31 ± 0.72
5.17 ± 0.91
0.277
Log HOMA-IR
2.63 ± 0.79
2.60 ± 0.91
0.866
2.69 ± 0.91
2.67 ± 0.78
0.906
2.65 ± 0.82
2.71 ± 0.75
0.511
Diabetic nephrology, n (%)
20 (20.8)
21 (21.8)
0.887
63 (0.33)
56 (0.29)
0.575
15 (17.1)
27 (30.6)
0.095
Diabetic retinopathy, n (%)
14 (14.6)
11 (11.4)
0.572
34 (0.18)
46 (0.24)
0.223
13 (14.7)
21 (23.8)
0.201
Diabetic neuropathy, n (%)
23 (23.9)
20 (20.8)
0.679
42 (0.22)
50 (0.26)
0.455
23 (26.1)
24(27.3)
0.896
Any diabetic vascular disease, n (%)
35 (36.4)
40 (41.6)
0.624
95 (0.50)
94 (0.49)
0.956
30 (34.1)
38 (43.1)
0.409
Changes in β-cell function
Islet β-cell function, as measured by fasting C-peptide, AUCins, AUCc-pep, AUCins/AUCglu and AUCc-pep/AUCglu, were all significantly higher in the OAD group than the insulin group and insulin plus OAD group (all P < 0.01) at baseline. After 4.5 (3.0-7.2) years of treatment, these indices in the OAD group were also the highest among the three groups. When comparing β-cell function before and after treatment, a decreasing trend of fasting C-peptide, fasting insulin, AUCins, AUCc-pep, AUCins/AUCglu and AUCc-pep/AUCglu was observed in all the three groups. No significant differences of decrement were observed among the three groups regarding the islet β-cell function indices. Table 3 and Figure 1 show the glycemic and β-cell function indices between before and after treatment among the three groups. Moreover, since treatment approaches change during the different disease states, results were analyzed based on similar disease duration. As shown in Table 4, significant differences in islet β-cell function were observed as the disease progressed among the three groups.
Figure 1 Levels of blood glucose, insulin and C-peptide during oral glucose tolerance test at baseline (solid line) and followed-up (dash line) between different anti-diabetic treatment groups.
A-C: Blood glucose; D-F: Plasma insulin; G-I: Plasma C-peptide; Data are mean ± SE. aP < 0.05. OCTT: Oral glucose tolerance test; OAD: Oral anti-diabetic drugs.
Table 3 Comparisons of β-cell function before and after anti-diabetic treatments.
Insulin
OAD
Insulin + OAD
P value
Fasting glucose (mmol/L)
Before
8.34 ± 2.69
6.91 ± 2.9
9.11 ± 4.3
0.023
After
7.62 ± 3.18
6.39 ± 2.7
7.99 ± 3.3
< 0.001
P value
0.876
0.941
0.475
Postprandial glucose (mmol/L)
Before
11.8 ± 4.9
12.2 ± 4.5
13.6 ± 5.3
0.019
After
12.6 ± 5.7
11.7 ± 3.9
12.7 ± 5.2
0.009
P value
0.295
0.975
0.169
HbA1c (%)
Before
8.6 ± 2.8
7.8 ± 2.3
9.6 ± 2.6
0.018
After
8.1 ± 2.2
7.7 ± 2.0
9.2 ± 2.3
< 0.001
P value
0.047
0.024
0.246
AUC glucose (mmol/L/h)
Before
43.5 (35.8-50.1)
40.5 (32.3-49.6)
46.6 (35.2-57.3)
0.031
After
42.6 (30.6-52.8)
39.5 (33.1-48.6)
45.3 (35.0-60.2)
0.003
P value
0.621
0.758
0.384
Fasting C peptide (nmol/L/h)
Before
0.64 (0.46-1.0)
0.8 (0.5-1.12)
0.58 (0.4-0.88)
0.002
After
0.51 (0.37-0.79)
0.71 (0.63-1.24)
0.47 (0.35-0.79)
< 0.001
P value
0.002
0.026
< 0.001
AUC C peptide (nmol/L/h)
Before
4.45 (2.73-5.81)
5.52 (3.65-8.06)
3.74 (2.16-5.42)
< 0.001
After
3.85 (3.32-5.22)
4.92 (4.28-8.02)
3.1 (2.04-4.73)
< 0.001
P value
0.153
0.294
0.047
AUC C peptide/glucose
Before
0.1 (0.06-0.17)
0.14 (0.08-0.23)
0.08 (0.05-0.125)
< 0.001
After
0.08 (0.04-0.13)
0.15 (0.1-0.21)
0.07 (0.05-0.1)
< 0.001
P value
0.532
0.735
0.405
Table 4 Changes of β-cell function after different anti-diabetic treatments according to disease duration.
Treatment
Disease duration (years)
Fasting insulin (pmol/L/h)
Fasting C-peptide (nmol/L/h)
AUC insulin (pmol/L/h)
AUC C-peptide (nmol/L/h)
Ins
0-1
65.4 ± 6.6
0.88 ± 0.08
695.7 ± 105.5
5.58 ± 0.57
1-5
104.0 ± 33.6
0.68 ± 0.05
731.0 ± 111.2
5.16 ± 0.43
5-10
95.5 ± 28.9
0.69 ± 0.06
628.3 ± 125.0
4.22 ± 0.34
10-20
72.6.0 ± 24.9
0.70 ± 0.07
550.6 ± 122.9
3.91 ± 0.37
20-30
93.1 ± 31.6
0.73 ± 0.15
605.7 ± 131.7
3.68 ± 0.51
OAD
0-1
64.7 ± 5.8
0.87 ± 0.04
696.9 ± 54.6
6.14 ± 0.27
1-5
77.0 ± 6.6
0.98 ± 0.07
761.1 ± 39.8
6.65 ± 0.25
5-10
62.7 ± 3.4
0.88 ± 0.03
687.8 ± 40.1
6.05 ± 0.25
10-20
98.8 ± 18.8
0.81 ± 0.03
740.1 ± 84.4
5.14 ± 0.20
20-30
96.8 ± 26.1
1.00 ± 0.13
709.5 ± 139.4
5.74 ± 0.65
Ins + OAD
0-1
80.6 ± 13.6
0.80 ± 0.07
715.2 ± 95.9
5.12 ± 0.48
1-5
76.6 ± 8.9
0.78 ± 0.03
597.1 ± 53.2
4.47 ± 0.23
5-10
89.2 ± 17.3
0.66 ± 0.02
638.0 ± 92.7
3.85 ± 0.17
10-20
84.4 ± 7.8
0.70 ± 0.05
533.9 ± 33.4
3.85 ± 0.16
20-30
204.2 ± 93.2
0.75 ± 0.06
542.0 ± 67.6
3.94 ± 0.31
P value
0-1
0.631
0.095
0.805
0.002
1-5
0.402
0.001
0.001
0.001
5-10
0.369
0.001
0.002
0.001
10-20
0.132
0.001
0.005
0.001
20-30
0.161
0.041
0.039
0.002
Initial phase of insulin secretion and peak insulin secretion
The early phase of insulin secretion reflected by the ΔC30/ΔG30 was significantly higher in the OAD group than the insulin group and insulin plus OAD group both before and after treatment (Table 5). There were no obvious changes regarding ΔC30/ΔG30 between before and after 4.5 years of treatment among the three groups. Moreover, the ratio of delayed inulin secretion responses before and after treatment in the three groups was calculated. As shown in Figure 2, all three groups had an increased ratio of delayed inulin secretion response after 4.5 years of observation. The percentages of delayed inulin secretion response in the different treatments were as follows: Insulin monotherapy (51.8% to 79.1%), OAD monotherapy (60.3% to 67.3%), and insulin plus OAD therapies (64.1% to 66.7%).
Figure 2 Percent of delayed inulin secretion response between baseline and followed-up after different anti-diabetic treatments.
Ins: Insulin therapy; OAD: Oral anti-diabetic drugs.
Table 5 Comparisons of β-cell response, insulin sensitivity and insulin resistance before and after different anti-diabetic treatments.
Insulin
OAD
Insulin + OAD
P value
C peptide index [ΔC30/ΔG30]
Before
0.095 (0.025-0.14)
0.103 (0.04-0.17)
0.076 (0-0.07)
0.235
After
0.125 (0.03-0.182)
0.1 (0.03-0.27)
0.067 (0.02-0.12)
< 0.001
Log HOMA-β
Before
5.92 ± 0.17
5.91 ± 0.08
5.49 ± 0.08
< 0.001
After
5.47 ± 0.11
5.73 ± 0.08
5.32 ± 0.08
< 0.001
Log HOMA-IR
Before
2.63 ± 0.13
2.68 ± 0.08
2.76 ± 0.07
0.933
After
2.89 ± 0.15
2.79 ± 0.09
2.886 ± 0.08
0.175
Matsuda index (ISI)
Before
17.89 ± 7.6
13.4 ± 3
16.24 ± 4
< 0.001
After
14.43 ± 6.1
11.9 ± 2.8
14.1 ± 11.3
< 0.001
Insulin resistance indices
The islet β-cell function, insulin sensitivity and insulin resistance measured by HOMA-β, HOMA-IR and Matsuda index were shown in Table 5. Similarly, β-cell function reflected by the HOMA-β and insulin sensibility reflected by the Matsuda index were all decreased among the three groups, while insulin resistance reflected by the HOMA-IR was all increased in the three groups.
DISCUSSION
In this longitudinal study, we demonstrated that islet β-cell function in elderly patients with T2DM was all decreased independent of anti-diabetic therapy by insulin, OAD, or their combination after a mean observation of 4.5 years. To our knowledge, this is the first study highlighting the effect of different anti-diabetic regimens on islet β-cell function in an exclusive population of elderly Chinese patients with T2DM.
Islet β-cell function preservation is an important issue in the management of T2DM. Many previous studies have reached inconsistent conclusions (positive, neutral, or negative) regarding the effect of anti-diabetic therapies on β-cell function preservation[4,7,13]. However, most of the positive effects diminished or were even lower than baseline after drug withdrawal[14-16]. Moreover, most currently available studies which assessed the β-cell function preservation had focused on the middle-aged population. For example, the UKPDS enrolled participants aged 25 to 65 years and concluded that pancreatic β-cell function in patients with T2DM deteriorates over time, leading to worsening metabolism and increasingly anti-diabetic requirements[13]. Studies by Weng et al[4] on patients with a mean age of 50.0 ± 10.5 years showed that insulin therapy in newly diagnosed patients with T2DM had a favorable effect on β-cell function preservation. A meta-analysis which summarized seven studies of post-intensive insulin therapy for patients with T2DM showed an increase in HOMA-β as compared with baseline. Notably, all the included studies recruited participants aged between 45.8 and 58.7 years[5]. The RISE study studied a group of young onset patients with newly diagnosed IGT and demonstrated that treatment with glargine or metformin did not halt the progressive deterioration of β-cell function[7,8]. Currently, studies on β-cell function in an exclusively elderly population are valuable. This present study showed the changes in β-cell function treated with different glucose-lowering regimens in elderly patients with T2DM. Results showed that the β-cell function deteriorates in all treatment modalities, indicating that β-cell function in these populations may distinctly differ from their young counterparts. This phenomenon is largely attributed to aging per se. The age-related impairment of β-cell function has been linked to many factors such as mitochondrial dysfunction[17,18]; reduced GLUT2 levels[19]; impaired Ca++ handling[20]; increased autophagy[21]; and reduced expression of beta-cell-specific genes and transcription factors[19]. Since aging carries additional risks for β-cell dysfunction and insulin resistance, it is challenging to halt the deterioration of β-cell function in elderly patients with T2DM.
In this study, patients with OAD treatment were found to have less β-cell function reduction over insulin or insulin plus OAD treatment, indicating that OAD treatment may provide better β-cell function preservation. However, these did not reach statistical significance because of the relatively small sample sizes. Such results can be ascribed to the worse baseline β-cell function in the insulin group and insulin plus OAD group while the better baseline β-cell function in the OAD monotherapy group. Firstly, patients who take insulin plus OAD therapy had a higher level of fasting glucose, postprandial glucose and HbA1c at both baseline and follow-up, indicating that these patients are more prone to encounter glucotoxicity, which is known to be associated with poor β-cell function preservation[22]. Additionally, some patients in the insulin plus OAD group received only OAD monotherapy or insulin monotherapy at the beginning of the study; however, they received one more therapy because of uncontrolled hyperglycemia during follow-up. These results demonstrated that such patients had worse glycemic variability, which is both a cause and consequence of poor β-cell function[23-25]. Thirdly, better β-cell function preservation in patients with OAD monotherapy may be due to better baseline β-cell function since worse baseline β-cell function per se is associated with worse metabolic control and higher hyperglycemia or hypoglycemia events[26].
Notably, unlike many studies which showed a protective effect of insulin therapies or insulin plus OAD for β-cell function preservation[5,27], outcomes in this study demonstrated that β-cell function deteriorates irrespective of the insulin therapies in elderly patients with T2DM. This phenomenon can be attributed to the following reasons. The observation period in the present study lasted for a mean duration of 4.5 years, which is much longer than that in previous studies that demonstrated the favorable effects of insulin therapy for β-cell preservation[5]. It remains unknown whether the positive effects in these studies persist after 4.5 years of observation. In contrast, more than 60% of the participants in this study had a mean disease duration of approximately 3 years. Moreover, even newly diagnosed patients with T2DM in older adults may have long-term diabetes at the time of diagnosis. Therefore, the mass of β-cell, the capacity of β-cell function, the insulin sensitivity, and the response ability to hypoglycemic regimens may be aggravated more than in middle-aged early-staged patients. Lastly, long duration of insulin treatment may provide rigorous glycemic control; however, long-term exogenous insulin exposure in older adults may have also led to additional adverse effects such as weight gain, insulin resistance and hypoglycemia events[28,29], which may offset the benefit of insulin-induced euglycemia and add extra burden to β-cell function. Therefore, insulin intervention in this population may pose an uncertain net balance of benefit and harm for β-cell function.
This study had some limitations. First, this was an observational study rather than a randomized controlled trial. Second, because human aging is accompanied by a decline in organ function, it would be more convincing to compare the results with baseline data from non-diabetic elderly individuals. However, we could not include a placebo arm because it was unethical for elderly patients with T2DM left untreated, nor was it feasible to test β-cell function in healthy, non-diabetic elderly individuals. In future studies, elderly patients without diabetes should be included for comparison. Third, 62.3% of the 745 patients in this study were not newly diagnosed; therefore, the baseline β-cell function before treatment could not be accessed in these patients. Fourthly, this study was conducted in a single (Asian) racial group, and the results may not be generalizable to other groups. Fifthly, Although DPP-4 inhibitors became available in the first decade of the 21st century, and two important new classes of antidiabetic medications—SGLT-2 inhibitors and GLP-1 receptor agonists—entered the market in the second decade, these drugs were not considered first-line options and routinely used at those times. Additionally, due to local insurance policy constraints, both doctors and patients preferred the medications mentioned in the manuscript, resulting in a lack of information and assessment regarding the impact of these newer medications on pancreatic function. Sixthly, therapeutic inertia may be exist due to the followed reasons: (1) The patients included in this study were all hospitalized due to poor blood sugar control, which implies that their metabolic status at the time of admission was often poor. This initial condition could lead to elevated HbA1c levels; (2) All included patients in this study were elderly. Pancreatic function in these population may be compromised, leading to greater blood sugar variability. This might contribute to the higher oscillation of the average HbA1c percentage; (3) While intensive glycemic control can improve blood sugar management in elderly patients, it also significantly increases the risk of hypoglycemia. Additionally, intensive glycemic control may also raise the risk of cognitive decline such as dementia. Therefore, clinicians might take individual patient circumstances into account, balancing glycemic control with the occurrence of hypoglycemic events, which could also contribute to the therapeutic inertia; and (4) Elderly diabetic patients often present with a higher prevalence of diabetic vascular complications. These complications not only affect the overall health status of the patients but may also complicate blood sugar control and influence treatment strategies, further leading to therapeutic inertia in diabetes management. Nevertheless, this study’s results reveal that the β-cell function in elderly patients with T2DM declines over time independent of insulin or OAD treatments. Older adults may differ distinctly from middle-aged or young populations in both physiology and pathophysiology, and there is extensive variability within the T2DM population in terms of clinical presentation, psychosocial environment, and resource availability. Therefore, it is difficult to delay the inexorable decline of β-cell function through single pharmacological agents. The management of β-cell dysfunction in older adults should be individualized, considering multiple factors, such as living situation, overall health, cognitive functions, and the presence of comorbidities.
CONCLUSION
This longitudinal observational study revealed that islet β-cell function in Chinese elderly patients with T2DM progressively declines regardless of insulin supplement or insulin plus OAD treatments.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C, Grade D
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade B
P-Reviewer: Cai L; Cigrovski Berkovic C; Dąbrowski M; De S; Zhao K S-Editor: Lin C L-Editor: A P-Editor: Zhao S
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