Diabetes Is Rooted In Insulin Toxicity – Part Two

Majid Ali, M.D.

Diabetes Begins 15–20 years before it is diagnosed


 

Text Reproduced From An Important Published Paper
Article: Hulsegge G, Spijkerman AMW, van der Schouw, et al. Trajectories of metabolic risk factors and biochemical markers prior to the onset of type 2 diabetes: the population-based longitudinal Doetinchem study.  Nutrition & Diabetes (2017) 7, e270; doi:10.1038/nutd.2017.23

Background:
Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15–20 years.
Methods:
A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose 11.1mmoll−1) and 2130 controls were identified in a prospective cohort between 1987–2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations.
Results:
Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15–20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5–8% over 15 years, whereas the increase among persons without type 2 diabetes was 0–2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women.
Conclusions: 
Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15–20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

Text continued
Although it has been well established that adverse levels of risk factors often develop early in life and are maintained over time,123456 it is not fully understood how they progress to type 2 diabetes (T2D). For example, T2D might be preceded by a gradual accumulation of the adverse effects of risk factors starting at a young age, or by a relatively sudden deterioration in risk factors before disease onset, or by a combination of both. The comparison of long-term trajectories of risk factors between those who do and those who do not develop T2D may help to identify at which time point these trajectories start to deviate before the development of overt disease. Such insight into the timing and the extent of pathophysiological changes before symptoms occur may provide indications for the optimal timing of preventive actions. Trajectories of BMI and waist circumference are of particular importance since these are strong modifiable risk factors of T2D.78 Other relevant factors associated with T2D include glucose levels,9 β-cell function,10 insulin resistance,10 blood pressure,8lipids,8 liver fat markers,1112 markers of chronic inflammation13 and kidney function.14
Several studies have described gradual changes in β-cell function, insulin resistance, fasting glucose and 2-h post-load glucose many years before diagnosis of T2D with steeper unfavourable changes 3–5 years before diagnosis.1516171819 Only a few studies, mainly among men, have examined progressive changes of other risk factors, such as BMI, but so far findings have been inconsistent. The Whitehall II study showed that adults who developed T2D had similar trajectories of BMI and C-reactive protein (CRP) but more unfavourable trajectories of systolic blood pressure and high-density lipoprotein (HDL) cholesterol compared with adults without T2D, over a period of ~14 years.2021 In contrast, a small study of 177 men observed larger changes in BMI, but no differences in blood pressure, HDL cholesterol and liver fat markers in men who developed impaired fasting glucose compared with men who did not, over a 9-year period.22 A short-term study (that is, over 1.5 years) observed differences in changes of alanine aminotransferase (ALT) and triglycerides but not in blood pressure, total cholesterol and HDL cholesterol between high-risk men with incident T2D and controls.17
A longer follow-up period in a population-based study and inclusion of other metabolic risk factors and biochemical markers is needed for more insight in the physiological changes preceding the onset of T2D. There is also a need to investigate differences between men and women since previous studies reported several sex-related differences in the associations of risk factors such as systolic blood pressure, HDL cholesterol and uric acid with T2D.2324 Therefore, we examined whether trajectories of metabolic risk factors and biochemical markers among initially healthy men and women differed for those who developed T2D and those who did not over a period of up to 15–20 years.

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