ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun. 2020;11(1):1841. Published 2020 Apr 15. doi: https://pubmed.ncbi.nlm.nih.gov/32296068/

This study by Kullmann et al. investigated the impact of brain insulin resistance on medium and long-term changes in body weight and body fat in adults at high risk for T2DM, undergoing a 24-months lifestyle intervention program (n =28 at the 24-months follow-up, n =15 at the 9-years follow-up). Study participants underwent two hyperinsulinemic-euglycemic glucose clamps with cerebrocortical activity assessed by magnetoencephalography before and during the clamps. Subjects with high brain insulin sensitivity lost significantly more body weight (ø -7.2 kg) after two years of lifestyle intervention and also showed a pronounced reduction of visceral adipose tissue (ø -1.3 l) compared to subjects with brain insulin resistance. Importantly, baseline brain insulin sensitivity was associated with lower regain of body weight and smaller increases in total and visceral fat mass in the long-term follow-up spanning a period of 9-years. To further test for the role of CNS insulin responsiveness as a potential determinant of body fat distribution, the investigators obtained data on brain insulin sensitivity using fMRI of the hypothalamic region with administration of intranasal insulin in a cross-sectional cohort (n =112) also participating in the aforementioned lifestyle intervention program. Better hypothalamic insulin responsiveness was significantly associated with less visceral adipose tissue independent of age, sex, and BMI. No association could be found for hypothalamic insulin sensitivity and subcutaneous adipose tissue. Hypothalamic insulin response was furthermore associated with lower HbA1c, lower fasting glucose and lower HOMA-IR.

Insulin resistance at the level of skeletal muscle or the liver is a hallmark feature of the pathogenesis of type 2 diabetes mellitus and the name-giving component of the metabolic or insulin resistance syndrome. Over the past three decades, detailed knowledge has been amassed about the pathophysiology of impaired insulin signaling in many types of tissues under conditions of overfeeding and obesity, and its consequences for substrate flux and development of obesity-associated comorbidities (1). But what about the brain? Glucose utilization in the CNS does not depend on insulin, but this does not imply that brain functioning is unaffected by insulin signaling. Indeed, insulin receptors are expressed abundantly in the brain with highest expression rates in humans seen in cortical and subcortical regions, the cerebellum and also prominently in the hypothalamus (2). Insulin exhibits anorexigenic properties when administered to rodent brains. Experimental data suggests that brain insulin in humans affects lipid metabolism in liver and visceral adipose tissue (3, 4) and also improves whole body insulin sensitivity by stimulating peripheral glucose uptake and suppressing endogenous glucose production (5–7). Interestingly, brain sensitivity to insulin shows considerable inter-individual variability. Obese subjects seem to be more often affected by ‘brain insulin resistance’, although it remains unclear whether this observation can be interpreted as a consequence of obesity or as a potential causal mechanism that promotes weight gain and ectopic fat accumulation (8).

In conclusion, the results of Kullmann et al. add an important piece to the puzzle of obesity pathogenesis, underscoring the role of brain insulin sensitivity as a determinant of body fat distribution and predictor of long-term changes in subcutaneous and visceral fat accumulation, which will very likely have important implications for an individual’s cardiometabolic risk.

References:

1. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 2016;126:12–22.

2. Kullmann S, Kleinridders A, Small DM, Fritsche A, Häring HU, Preissl H, Heni M. Central nervous pathways of insulin action in the control of metabolism and food intake. Lancet Diabetes Endocrinol 2020;8:524–534.

3. Iwen KA, Scherer T, Heni M, Sayk F, Wellnitz T, Machleidt F, Preissl H, Häring HU, Fritsche A, Lehnert H, Buettner C, Hallschmid M. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J Clin Endocrinol Metab 2014;99:E246–51.

4. Gancheva S, Koliaki C, Bierwagen A, Nowotny P, Heni M, Fritsche A, Häring HU, Szendroedi J, Roden M. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 2015;64 (6):1966–1975.

5. Heni M, Wagner R, Kullmann S, Veit R, Mat Husin H, Linder K, Benkendorff C, Peter A, Stefan N, Häring HU, Preissl H, Fritsche A. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 2014;63 (12):4083–4088.

6. Dash S, Xiao C, Morgantini C, Koulajian K, Lewis GF. Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes 2015;64 (3):766–774.

7. Heni M, Wagner R, Kullmann S, Gancheva S, Roden M, Peter A, Stefan N, Preissl H, Häring HU, Fritsche A. Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men. Diabetes 2017;66 (7):1797–1806.

8. Häring HU. Novel phenotypes of prediabetes. Diabetologia 2016;59 (9):1806–1818.