Clinical Significance of the Maximum Body Mass Index Before Onset of Type 2 Diabetes for Predicting Beta-Cell Function

Harutoshi Ozawa; Kenji Fukui; Sho Komukai; Yoshiya Hosokawa; Yukari Fujita; Takekazu Kimura; Ayumi Tokunaga; Junji Kozawa; Hiromi Iwahashi; Iichiro Shimomura

Disclosures

J Endo Soc. 2020;4(4) 

In This Article

Discussion

This study revealed two new findings. First, the MBBO was independently correlated with CPI and could predict the insulin secretion capacity at diagnosis. Second, MBBO did not seem to affect the rate of CPI decline during treatment for poor glycemic control, while BMI on admission did. Although there have been some reports in which the relationship between BMI and insulin secretion capacity was investigated, this is the first study to clarify the clinical significance of MBBO for predicting beta-cell function.

Some previous reports have shown that the rate of insulin secretion capacity decline was higher in diabetic patients with obesity than in those without obesity.[6,7,13] Our study also showed similar results in the analysis using BMI on admission. This result suggested that obesity might accelerate the impairment of beta-cell function after diagnosis, probably through the increased load on beta cells due to insulin resistance,[14,15] leading to beta-cell apoptosis through oxidative stress, endoplasmic reticulum stress or lipotoxicity.[16,17] In contrast, MBBO did not affect the rate of beta-cell function decline in this study. When we performed multiple regression analysis dividing patients into two groups based on MBBO (MBBO ≥ 25 kg/m2 and MBBO < 25 kg/m2), we obtained the same results as those obtained in the analysis of BMI on admission (Table 4). These data indicate that MBBO does not affect the rate of beta-cell function decline after the diagnosis of type 2 diabetes mellitus.

In addition, our study revealed that the estimated CPIs at diagnosis were higher in patients who had a higher MBBO. Together with the fact that there was no difference in the rate of CPI decline regardless of the MBBO, we could predict the time when the patient would reach insulin depletion using MBBO. Because this timepoint can be affected by the BMI after diagnosis, it is very important for the preservation of beta-cell function to decrease a patient's BMI during treatment after diagnosis, regardless of the MBBO.

Hypoglycemic agents might also affect the rate of CPI decline. In fact, thiazolidinedione has been reported to exert a more favorable effect than sulfonylurea on maintaining beta-cell function.[18] In this study, various hypoglycemic medicines were used among subjects before admission. Even when we also performed multiple linear regression analysis after adjustment for medications used before admission, CPI proved to be correlated with the duration of diabetes and MBBO independently, and the interaction between diabetes duration and MBBO had no significant effect (Table 5, Model A). Although whether individual hypoglycemic agents might affect the rate of CPI decline could not be evaluated in this study, we found the same correlation between MBBO and CPI independently, regardless of the usage of hypoglycemic agents before admission.

In addition, the measurement of CPI might be affected by the use of insulin secretagogues or basal insulin at evaluation. Even when we performed multiple linear regression analysis after adjustment for the use of these medications at evaluation, CPI was proven to be independently correlated with the duration of diabetes and MBBO, and the interaction between diabetes duration and MBBO had no significant effect (Table 5, Model B). Thus, the same results were obtained regardless of the use of these medications at evaluation, indicating that our conclusion would be the same.

While CPI is obtained from fasting insulin, ΔCPR of glucagon load test is one of the useful and direct indicator for dynamic insulin secretion capacity.[19] In our previous study, relative beta cell area was correlated with both CPI and ΔCPR.[11] Glucagon load test was performed in 299 patients of 410 patients in our study, and ΔCPR was defined as increment in serum CPR level at 6 minutes after intravenous injection of 1 mg glucagon. To evaluate whether CPI is a reliable indicator of beta cell function, we confirmed a correlation of CPI and ΔCPR. In 299 patients with glucagon load test, CPI was strongly correlated with ΔCPR (r = 0.62, P < .0001). We divided these participants into 3 groups (low group: MBBO < 25; n = 57, intermediate group: 25 ≤ MBBO < 30; n = 119, high group: 30 ≤ MBBO; n = 123). We also divided participants into 2 groups: one was BMI < 25, and the other was 25 ≤ BMI. In 299 patients, mean ages was 62 ± 14 years. Mean diabetes duration was 11 ± 10 years, and there was no difference in duration among these three MBBO groups. In each MBBO group, CPI was 0.58 in low group, 1.0 in intermediate group, and 1.2 in high group. ΔCPR was 1.2 ng/ml in low group, 1.7 ng/mL in middle group, and 1.9 ng/mL in high group. We performed multiple linear regressions for ΔCPR as a dependent variable and obtained almost the same results. A multiple linear regression analysis using MBBO revealed an interaction effect between the low MBBO group and the high MBBO group (Table 6, Model 1). When we paid attention to the rate of ΔCPR decline, there was no difference among the three groups. In subgroup analyses, multiple linear regressions adjusting for age and sex indicated an annual decline rate of ΔCPR as the coefficient of duration/intercept in each group (Table 6, subgroup analyses by MBBO group). The decline rate of the low MBBO group was 1.6%, that of the intermediate MBBO group was 1.2%, and that of the high MBBO group was 1.6%. Furthermore, we performed a multiple linear regression analysis using BMI on admission instead of MBBO. The P value of this interaction was .0024, indicating that the interaction between diabetes duration and BMI on admission had a significant effect (Table 6, Model 2). The decline rate of the low BMI group was 1.0%, and that of the high BMI group was 1.8%, suggesting that the decline rates of ΔCPR were different in the BMI on admission subgroups (Table 6, subgroup analyses by BMI group). These analyses and strong correlation between CPI and ΔCPR revealed the usefulness of CPI for evaluating insulin production capacity.

This study had some limitations. First, it was a retrospective cross-sectional observational study. Prospective longitudinal studies with evaluation of the effects of treatments are necessary to clarify the actual change in individual patients' CPIs. Second, we excluded patients whose maximum BMI was reached after the diagnosis of type 2 diabetes mellitus from this study. Because it is conceivable that a high BMI after diagnosis will accelerate the impairment of beta-cell function, the rate of CPI decline would be higher in each group divided by MBBO if we included patients who reached their maximum BMI after diagnosis. Further study is needed to clarify this issue. Third, we struggled to control patients' glucose level in their hospital, but a part of patients did not had good control. This fact was one of our study limitations.

In conclusion, MBBO is a factor that is independently correlated with beta-cell function, may estimate insulin secretion capacity at onset, and may possibly predict a patient's insulin secretion capacity under appropriate health control. In addition, MBBO does not affect the rate of insulin secretion capacity decline, although BMI on admission for treatment of poor glycemic control does. It is important for the preservation of beta-cell function to decrease a patient's BMI during treatment, regardless of the MBBO.

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