The spectrum of exogenous insulin requirement in people living with type 1 diabetes: A cross‐sectional analysis

The main pathophysiology of type 1 diabetes (T1D) is the autoimmune destruction of pancreatic beta cells leading to minimal or no production of insulin.1, 2 Comparatively, insulin resistance (IR) is a key pathophysiologic driver of type 2 diabetes.2 Nevertheless, there has been longstanding evidence of IR in T1D, including IR studies using the gold standard euglycaemic-hyperinsulinemic clamp,3 or the estimated glucose disposal rate (eGDR)4, 5 as a marker of IR. Calculations for eGDR include three parameters that are also part of the diagnostic criteria for the metabolic syndrome which is also driven by IR6-8: (1) an indicator of abdominal obesity (waist-to-hip ratio, waist circumference, or body mass index); (2) presence of hypertension (HTN); and (3) HbA1c. Abdominal obesity, HTN, and a higher HbA1c will result in a lower eGDR, which represents more severe IR.3-7 A lower eGDR in T1D has been associated with more microvascular and macrovascular complications and higher all-cause mortality.4-7, 9 For people living with type 1 diabetes (PwT1D), their exogenous insulin requirement, which is their insulin total daily dose per kilogram of body mass (TDD/kg), has also been viewed as an indicator of IR.1 In real world settings, we observe that to attain the common HbA1c target of <7%, PwT1D with similar obesity and HTN can require a wide range of insulin TDD/kg treatment. However, the eGDR calculation uses the HbA1c irrespective of the insulin TDD/kg.4-7, 9 This raises a concern that the severity of chronic peripheral hyperinsulinemia which can increase IR by downregulating insulin signalling pathways,1 is not directly accounted by the eGDR. However, the exogenous insulin requirement (insulin TDD/kg) could be an important indicator of the extent of this chronic peripheral hyperinsulinemia.1, 10 The objective of this hypothesis-generating study was to explore the spread of insulin TDD/kg in PwT1D using multiple daily injection (MDI) insulin versus PwT1D using an insulin pump, with respect to HbA1c categories and by eGDR severity categories. The BETTER registry11, 12 is a large Canadian cohort of PwT1D who completed online surveys. PwT1D reported the data used for this study, and the details are in the Supporting Information. We performed a cross-sectional analysis of adult PwT1D age 18 years or above who use an insulin pump or MDI insulin and answered the questions relevant to this study. We excluded PwT1D with diabetes for ≤2 years, which covers the “honeymoon phase” (the period of time when there is residual endogenous insulin production) in most people. To explore the spectrum of insulin TDD/kg, we presented the insulin TDD units/kg versus deciles of insulin TDD/kg for HbA1c categories and for eGDR severity categories. In people without diabetes, the pancreas of a 70-kg adult produces ~30 to 35 units of insulin per day, which is insulin TDD/kg ~0.4 to 0.5 units/kg.2, 13 Notably, for PwT1D, exogenous insulin is administered via a non-physiologic and less efficient subcutaneous route. Therefore, we interpreted insulin TDD/kg >0.50 units/day as the start of the IR spectrum. The calculation for eGDR4, 5 (mg/kg/min) = 19.02 − (0.22 × BMI) − (3.26 × HTN) − (0.61 × HbA1c) was performed using HbA1c 6.5%, 7.5%, 8.5%, and 9.5% for PwT1D reporting HbA1c ≤7.0%, 7.1%–8.0%, 8.1%–9.0%, and ≥9.0%, respectively. eGDR severity categories4, 5 from most severe IR to least IR were: <4.00; 4.00–5.99; 6.00–7.99; and ≥8.00. Statistical significance analyses are described in the Supporting Information. For every HbA1c category, there is a wide spread of insulin TDD/kg (Figure 1), which reflects the substantial heterogeneity in exogenous insulin requirements in PwT1D. Furthermore, PwT1D with higher HbA1c are mostly already taking higher insulin TDD/kg, which signals more IR compared with PwT1D with HbA1c ≤7.0%. However, despite this higher insulin TDD/kg, this still represents under-insulinisation: an underestimate of their exogenous insulin that would be required to attain the typical HbA1c goal ≤7.0%. Significant differences in PwT1D characteristics were only found in the MDI insulin group, where the higher HbA1c categories reported significantly less physical activity (minutes per week) and more nephropathy (Tables S1 and S2). The spectrum of insulin TDD/kg overlaps for all eGDR severity categories (Figure 2) for PwT1D. This finding implies that there is a wide range of the severity of chronic peripheral hyperinsulinemia for the PwT1D in each eGDR severity category. However, the extent of PwT1D's chronic peripheral hyperinsulinemia as a contributor to IR does not appear to be factored into the eGDR calculation. Comparatively, for all HbA1c categories and all eGDR severity categories, the maximum insulin TDD/kg in PwT1D on insulin pump is less than that in those on MDI insulin. Contributors to lower insulin TDD/kg for PwT1D on insulin pump include better absorption related to continuous exogenous insulin delivery and technological efficiencies of closed-loop or automated insulin delivery systems. There were a few significant differences yet no clear trends for the variables that reflected the socio-economic status for PwT1D using insulin pump vs. MDI insulin (Tables S1–S6). Significant differences in PwT1D characteristics across the eGDR groups were only detected for BMI and presence of HTN in the MDI insulin group and the insulin pump group (Tables S3 and S4). This is expected because the eGDR calculation includes the BMI and presence of HTN. The major limitation of this study was that there are many contributors to PwT1D's exogenous insulin requirements that were not adjusted for, including their diet quality and quantity of carbohydrate intake, concomitant medications that can increase or decrease their IR, and factors that compromise insulin absorption. The findings of our hypothesis-generating study can recommend for future studies in this field to explore the associations of these contributors to the spectrum of IR in PwT1D. Another limitation was that our survey collected HbA1c categories, and therefore we used a representative HbA1c in each category for the eGDR calculation. Since the eGDR calculation has a factor of 0.61 per 1% change in HbA1c, the eGDR could have been slightly over or under-estimated. However, this would not be expected to affect our finding of the substantial overlap in insulin TDD/kg across all eGDR severity categories. There is a wide spectrum of insulin TDD/kg for each HbA1c category, and each eGDR severity category. The eGDR calculation's HbA1c does not account for this spectrum of the exogenous insulin that is required to attain the HbA1c. The added value of the exogenous insulin requirement (insulin TDD/kg) compared to the eGDR for PwT1D is that insulin TDD/kg reflects each PwT1D's severity of chronic peripheral hyperinsulinemia exposure, which itself contributes to IR. An important implication of our results is that the exogenous insulin requirement, as assessed by insulin TDD/kg in the context of the HbA1c, could serve as a marker of each PwT1D's severity of chronic peripheral hyperinsulinemia. Insulin TDD/kg as an indicator of an individual's IR warrants further studies of its clinical usefulness in the care of PwT1D. Virginie Messier, Rémi Rabasa-Lhoret, and Cathy J. Sun designed the study, contributed to discussion, and wrote and reviewed the manuscript. Virginie Messier, Timothy Ramsay, and Cathy J. Sun analysed the data collected from the participants in the Canadian Type 1 Diabetes Better registry. Timothy Ramsay contributed to discussion and reviewed the manuscript. All authors approved the final version of the manuscript. Cathy J. Sun is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This study was supported by a research grant from Breakthrough T1D Canada to Rémi Rabasa-Lhoret. The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70467. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting Information. 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