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Background and aims: An important role of the CNS in the pathogenesis of type 2 diabetes (T2D) has been suggested and is supported by animal studies. The brain senses fluctuations in systemic glucose levels and modulates glucoregulatory hormones and autonomic nerve activity to balance glucose levels. We hypothesize that the brain’s setpoint for glucose is gradually shifted upwards in the development of T2D. The aim of this study was to investigate if the neuroendocrine response to varying glucose levels differ in overweight and insulin-resistant compared to control subjects.

Materials and methods: 30 subjects with no diagnosis of diabetes were recruited and allocated into two groups based on the median BMI: LO [BMI 23.4 kg/m2 (Range 18.9-26.9)] and HI [BMI 32.0 (27.0-48.7) kg/ m2 ]. Age and gender distribution were similar. On two separate occasions and in a randomized order, stepwise hypoglycemic (nadir 2.7 mM) and hyperglycemic (max +9 mM) clamps were performed with repeated measurements of hormones (glucagon, cortisol, ACTH, growth hormone), assessment of symptoms according to the Edinburgh Hypoglycemia Symptom Scale (ESS) and monitoring of heart rate variability (HRV). Mann-Whitney U-tests were used for group-wise comparisons.

Results: In HI vs LO the response to hypoglycemia was augmented for both cortisol [ΔAUC 12382 nM*min (IQR 7058;15705) vs 4792(- 1200;11498, p=0.045] and ACTH [ΔAUC 448.3 pM*min (373.5;702.0) vs 162.0 (125.3;397.5), p=0.015]. Subjects in HI reported higher peak ESS Scores [21 (19;23) vs 18 (14;21), p=0.045] during hypoglycemia. By contrast, subjects in HI had loss of suppression of PHF (an HRV marker of parasympathetic nerve activity) during hypoglycemia [0.035 ms2 log (- 0.353;0.188) vs -0.219 ms2 log (-0.476;-0.132), p= 0.024]. The above perturbations were independently associated with insulin resistance but not with obesity per se according to multilinear regressions (Table). During hyperglycemia there was a trend toward higher glucagon levels in HI vs LO [AUC 539.5 pM*min (336.9;617.2) vs 390.5 pM*min (244.5;476.2), p=0.085). Subjects in HI had lower mean PLF/ PHF ratio, a marker of balance between sympathetic and parasympathetic nerve activity [0.383 (0.260;0.568) vs 0.154 (0.081;0.299), p=0.005].

Conclusion: Overweight, insulin-resistant subjects had more symptoms during hypoglycemia and this was combined with central cortisol axis overactivity via pituitary ACTH release, altogether suggesting altered CNS responses. They also had less dynamic autonomic nerve activity. These neuroendocrine alterations were associated with insulin resistance independent of obesity, supporting a role of the brain in raising the glycemic setpoint in the development of T2D.