Low cerebrospinal fluid insulin levels in obese humans

Kern, Werner; Benedict, Christian; Schultes, Bernd; Plohr, F.; Möser, Andreas; Born, Jan; Fehm, Horst L.; Hallschmid, Manfred

doi:10.1007/s00125-006-0409-y

Cited by 126 publications

(111 citation statements)

References 9 publications

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“…Obese humans, however, whose plasma insulin levels are elevated as a result of peripheral insulin resistance, do not display parallel increases in CSF insulin levels, but rather have a decreased CSF:plasma insulin ratio [29]. Similar observations were made in animals with diet-induced [4] and genetic obesity [30].…”

Section: Central Nervous Insulin Resistancesupporting

confidence: 60%

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Hallschmid

Schultes

2009

Diabetologia

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Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an evergrowing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

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Section: Central Nervous Insulin Resistancesupporting

confidence: 60%

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Hallschmid

Schultes

2009

Diabetologia

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“…This outcome is strikingly different from the results in normal-weight men where the same treatment reduced hunger and induced a distinct loss of body fat and body weight. 16 It can be concluded that besides impaired blood-to-brain transport of insulin [11][12][13] that in our experiments was overridden by the intranasal administration of the compound, obesity is associated with central nervous resistance against the adiposity signal insulin not only in animals, but also in humans. Concordantly, intranasal insulin failed to acutely suppress food intake in obese men.…”

Section: Discussionmentioning

confidence: 61%

“…11,12 In humans, obesity appears to be associated with a comparable lack in CNS insulin. 13 Intranasal administration of insulin bypasses the bloodbrain barrier, increasing the concentration of the compound in cerebrospinal fluid without absorption into the blood stream. 14 Accordingly, intranasally administered neuropeptides have been shown to effectively accumulate in rat brain tissue.…”

Section: Introductionmentioning

confidence: 99%

Obese men respond to cognitive but not to catabolic brain insulin signaling

et al. 2007

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Context and objective: Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound. Design, subjects and measurements: Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day À1 ) over 8 weeks to two groups of 15 obese men each. Results: Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P40.50) and body fat (P40.44) in the obese subjects. However, in accordance with the effects in normalweight men, declarative memory and mood were improved (Po0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (Po0.01) and cortisol levels (Po0.04) was reduced. Conclusions: Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.

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“…A similar trend towards a limited increase in sympathetic activity in obese and type 2 diabetic patients has been reported during other tests, including deep breathing, exercise and oral glucose challenge [12,39,40], suggesting a reduction in sympathetic reserve when sympathetic activity is relatively high at baseline. A blunted sympathetic response may result from impaired insulin transport across the blood-brain barrier, which has been shown in experimentally induced insulin resistance in dogs [41], and from lower cerebrospinal fluid insulin levels, as reported in obese insulin-resistant humans [42]. In line with this, brain insulin resistance coexists with peripheral insulin resistance [43,44].…”

Section: Effects Of Insulin On Vagosympathetic Activitymentioning

confidence: 62%