Deciphering the Role of Age/Timing on Type 2 Diabetes in Major Chronic Disease Precision Prevention and Mortality from a Life Course Perspective

Abstract

The global disease burden of type 2 diabetes is substantial. There is a dramatically rising trend in incidence and prevalence of early-onset type 2 diabetes (diagnosed under 40 years of age), a more severe and aggressive phenotype characterized by exaggerated insulin resistance, rapid decline in β-cell function, aggressive disease course, poorer response to treatment, and potentially higher risk for complications. Also, here is a worrisome rising incidence of early-onset cancers across the globe, which is driven predominantly by obesity- and diabetes-related cancers. Mounting evidence has established a close link, epidemiologically and biologically, between type 2 diabetes and increased cancer incidence. To our knowledge, however, no prior study has evaluated the relationship between type 2 diabetes and risk of cancer according to their onset age and disentangled the influence of type 2 diabetes onset age and duration. Type 2 diabetes is also strongly associated with excess risk of death and loss in life expectancy. The timing of diagnosis is critical, given that early-onset type 2 diabetes manifests as a more severe and aggressive phenotype. Moreover, the occurrence of type 2 diabetes at earlier ages increases the duration of diabetes over the life course. However, existing evidence on type 2 diabetes onset age and duration in relation to mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full spectrum of onset ages, durations, and major causes of death. Furthermore, data on how type 2 diabetes onset age and duration shape life expectancy remain scarce. Suboptimal diet is the leading preventable cause of type 2 diabetes, with dietary insulinemic and inflammatory potential playing a pivotal role in its development. Identifying evidence-based optimal prevention strategies for type 2 diabetes is an urgent public health priority. The timing of dietary exposure across the lifespan may be critical in shaping type 2 diabetes risk. Despite this, no prior study has deciphered the influence of diet on type 2 diabetes risk across major life stages from a life course perspective. In Chapter 1, we addressed the following unanswered research questions: Does the age of type 2 diabetes onset have an influence on cancer risk beyond type 2 diabetes duration? Is the association between early-onset type 2 diabetes and cancer risk inherently stronger than that of later-onset type 2 diabetes? We prospectively investigated the associations between incident early- (diagnosed under the age of 40 years) and later-onset type 2 diabetes and early- (diagnosed before age 50) and later-onset cancer risk based on 228,073 eligible participants in two large longitudinal cohorts: the Nurses’ Health Study and Nurses’ Health Study II. We reported that early-onset type 2 diabetes was associated with a substantially increased risk of early-onset total cancer, diabetes-related cancer, and obesity-related cancer, particularly among individuals with a higher BMI at age 18. Early-onset type 2 diabetes was also associated with a higher risk of later-onset diabetes-related and obesity-related cancers, specifically among those with a higher BMI at age 18. Later-onset type 2 diabetes was associated with a slightly increased risk of later-onset total cancer, diabetes-related cancer, and obesity-related cancer. In analyses based on refined timing, the hazard ratios attenuated substantially with aging. These findings suggest that cancer prevention efforts tailored to early-onset type 2 diabetes patients may need to focus on individuals with a higher BMI during adolescence or emerging adulthood. The influence of early-onset type 2 diabetes on cancer risk may be inherently stronger than that of later-onset type 2 diabetes. In Chapter 2, we addressed the following unanswered research questions: What is the long-term magnitude of excess mortality risk and loss in life expectancy associated with type 2 diabetes across the full range of onset ages and durations, as well as the specific causes of death? Is the influence of early-onset type 2 diabetes on all-cause and cause-specific mortality risk and years of life lost greater than that of later-onset type 2 diabetes? We prospectively investigated these topics using data from 270,075 eligible participants in the Nurses’ Health Study, Nurses’ Health Study II, and the Health Professionals Follow-up Study. We reported that younger type 2 diabetes onset age and longer disease duration were associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy. The relative risk elevations declined rapidly with increasing type 2 diabetes onset age, though the absolute risk difference increased continuously. The influence of early-onset type 2 diabetes on mortality risk and years of life lost was stronger than that of later-onset type 2 diabetes. These findings highlight the imperative need for effective strategies in preventing or at least delaying the onset of type 2 diabetes in lowering mortality and improving life expectancy. In Chapter 3, we addressed the following unanswered research questions: What are the associations of dietary insulinemic and inflammatory potential with type 2 diabetes risk across major life stages? What are their joint associations across major life stages? What are the associations between changes in dietary insulinemic and inflammatory potential from adolescence to adulthood and the risk of type 2 diabetes? Does lowering dietary insulinemic and inflammatory potential have immediate benefits in reducing the risk of type 2 diabetes in adulthood, or is there a time lag before the benefits become apparent? Leveraging data from 40,135 eligible participants in the Nurses’ Health Study II, we prospectively investigated, from a life course perspective in women, the associations of dietary insulinemic and inflammatory potential across different major life stages—adolescence, premenopausal adulthood, postmenopausal adulthood—and changes and cumulatively over the lifetime with the risk of incident type 2 diabetes. Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores were derived from validated adulthood food frequency questionnaires administered every 4 years and validated high school questionnaire. We reported that, over the life course in females, high dietary insulinemic and inflammatory potential during both premenopausal and postmenopausal adulthood—but not adolescence—was independently associated with a substantially increased risk of type 2 diabetes. Individuals with high adulthood dietary insulinemic and inflammatory potential had similar magnitudes of lifetime risk elevation, regardless of their adolescent dietary insulinemic and inflammatory potential status. Adolescent dietary insulinemic and inflammatory potential were associated with a slightly increased risk of premenopausal type 2 diabetes. These findings suggest that adulthood represents the most critical time window for dietary interventions to reduce lifetime type 2 diabetes risk, although adolescent diet may influence the risk of premenopausal type 2 diabetes. Furthermore, our analysis approximating the potential time window underscores the important message that it is never too late to reduce type 2 diabetes risk by lowering dietary insulinemic and inflammatory potential, as higher dietary insulinemic and inflammatory potential in adulthood were associated with an increased risk of type 2 diabetes with a very short time lag.