Neuroscience& BiobehavioralReviews.Vol. 15, pp. 243-258. v Pergamon Press plc. 1991. Printed in the U.S.A.

0149-7634/91 $3.00 + .00

Insulin in the Cerebrospinal Fluid C A R L O S R. P L A T A - S A L A M , ~ N

School o f Life and Health Sciences, University of Delaware, Newark, DE 19716 R e c e i v e d 1 1 M a y 1990

PLATA-SALAMAN. C. R. Insulin in the cerebrospinalfluid. NEUROSCI BIOBEHAV REV 15(2) 243-258, 1991.--The presence, distribution and specific localization of insulin and its receptors in the central nervous system (CNS) have been described in numerous reports. Insulin in the CNS appears to be similar to pancreatic insulin by biochemical and immunological criteria. While the presence of insulin in the cerebrospinal fluid (CSF)--an essential neurohumoral transport system--has been widely reported, the available information is fragmented and therefore it is difficult to determine the significance of insulin in the CSF and to establish future research directions. This paper presents an integrative view of the studies concerning insulin in the CSF of various species including the human. Evidence suggests that insulin in the CSF and brain may be the result of local synthesis in the CNS, and uptake from the peripheral blood through the blood-brain barrier and circumventricular organs. The passage of insulin from the peripheral blood through the blood-brain barrier may be mediated by a specific transport system coupled to insulin receptors in cerebral microvessels. The transfer of insulin from the peripheral blood through the circumventricular organs is not specific and may depend on simple diffusion. Slow access of insulin to brain interstitial fluid adjacent to the blood-brain barrier and circumventricular organs may be followed by selective transport to other brain sites and into the ventricular-subarachnoideal CSF. It has been hypothesized that the choroid plexuses, which constitute the blood-CSF interface, might be a nonspecific pathway for rapid insulin transport into the CSF. Insulin may also pass from the CSF into the peripheral blood via absorption into the arachnoid villi. This evidence indicates that insulin may be transported in both directions between the CSF-brain and the peripheral blood. Evidence also suggests that the presence of insulin in the CSF is of pivotal importance for its neurophysiological or neuropathophysiological significance. Insulin Review

Central nervous system Peptide

Brain

Cerebrospinal fluid

Blood-brain barrier

Circumventricular organs

bioassay, and neutralization of bioactivity by anti-insulin antibodies (16, 84, 112). However, the proposal of immunoreactive insulin as authentic insulin requires further verification (see below). The CSF/plasma ratio of insulin in the developing rabbit (70) is greater than in the rat (141). It has been proposed that a CSF/ plasma insulin ratio greater than 3% indicates either selective transport across the blood-brain barrier (BBB) and the circumventricular organs (CVOs) (141), and/or direct neurosecretion of insulin into the CSF. However, many other factors such as distribution, sequestration, and degradation of insulin within the central nervous system (CNS) may influence this ratio. In the developing rabbit, the BBB receptor transport activity for insulin is high in brain capillaries (60,70), so the greater than 3% CSF/plasma insulin ratio and brain insulin content observed in newborns is derived from the augmented activity of the neonatal BBB insulin receptor-transport system (see below).

INSULIN and its receptors are widely but unevenly distributed in the nervous system of various species, including the human. The presence, distribution and specific localization of insulin and its receptors in the nervous system have been described in numerous reports [see (1, 16, 35, 57, 74, 82, 86, 99, 111, 112, 148, 200, 201, 235)]. While the presence of insulin in the cerebrospinal fluid (CSF) has been widely reported, the available information is fragmented and therefore it is difficult to establish its regulation and physiological or pathophysiological significance. This review presents an integrative view of the studies concerning insulin in the CSF. INSULIN IN THE CEREBROSPINAL FLUID Insulin has been detected in the CSF of various mammals (Table 1). These values, in general, are multifold lower than the values of insulin in brain reported to be between 1 and 6 ng insulin g wet weight (35, 112, 136); plasma insulin levels are typically 3000 IxlU/ml) in neonatal pups

116

123

49

B) Negative reports Not detected in blood Not detected in blood No change in plasma insulin No change in plasma insulin or glucose

217 31,32 230 227

Abbreviations: AF, anterior fontanelle; CSF, cerebrospinal fluid; CVOs, circumventricular organs; IC, intracistemal; ICa, intracardial; IP, intraperitoneal; IV, intravenous; LCV, lateral cerebral ventricle; SC, subcutaneous; IIIV, third ventricle. See text for description.

food intake in rats (23, 69, 94, 133, 154) and baboons (227). Insulin in the CSF may also facilitate other satiety factors. For example, the efficacy of cholecystokinin in reducing meal size was greater when CSF insulin was increased in dogs (233a) and baboons (68). Various action mechanisms for insulin suppressing food intake have been proposed (154,233a), but the precise mechanisms are unknown. For further discussion see (46, 150, 152, 154, 202, 227, 229, 231, 233). It is also speculated that CSF insulin may participate in other CNS functions. Evidence obtained following ICV administration of insulin (Table 3) suggest other potential CNS actions involving: 1) metabolic processes (4--6, 8, 31, 32, 36, 90, 123, 129, 147, 179, 182, 185, 191, 198); 2) protein synthesis and growth activity (167); 3) the regulation of the hypothalamic-pituitary-hormonal axis (2,131); 4) neurochemical (catecholamine and other amines) turnover (114, 115, 173); 5) the autonomic nervous system (30, 32, 91, 123, 194, 195, 198, 220, 226); and 6) changes in neuronal electrical activity (217). It is important to note that these effects observed after the central administration of insulin

do not imply a neurophysiological action of insulin. Many other effects of insulin on the CNS have been reported, but their description is beyond the scope of this manuscript. Future research will establish the physiological significance of insulin in the CSF and CNS. INSULIN IN THE CEREBROSPINAL FLUID: SUMMARY

1) The origin of insulin in the CNS is a controversial issue. There is evidence in favor and against insulin synthesis in the CNS. It is hypothesized that insulin in the CSF may be the result of local synthesis in the CNS and/or uptake from the peripheral circulation. 2) Insulin may be able to pass through the BBB by a saturable transport mechanism (11, 76, 122, 130). The participation of other carrier systems in the transport of insulin through the BBB are also possible. The cerebral blood vessels bind blood-borne insulin with specificity and the endothelial cell is the site for the binding interaction (204,205). The transport of insulin across the

250

PLATA-SALAM,,~

TABLE 3 EFFECTS OF INSULIN ADMINISTRATION INTO THE VENTRICULAR SYSTEM OR SUBARACHNOID SPACE*t

Species

Administration Route

Chicken

IC

Amounts of Insulin 1 IU/kg

Mouse

LCV

Mouse Mouse

LCV LCV

6.3, 63 and 625 mlU 0.5 ixg 0.5 p.g

Rat

LCV

0.2 IU

Rat

LCV

160-480 mlU

Rat

LCV

10.3 pmol/I

Rat

LCV

100 p.IU/I h

Rat

LCV

10 ptlU

Rat

LCV

0.1 IU/h/7 days

Rat

LCV

45-600 ng/day/10 days

Rat

LCV

0.5-2.5 IU/day/7 days

Rat

liD/

5 p.IU/min

Rat

liD/

5 p.IU/min/60 min

Rat

liD/

600 mlU

Rat

liD/

70--480 pmol

Rat

liD/

Rat

liD/

0.5 and 2.0 mlU 2 mlU/day/7 days

Effect Decreased blood glucose (reduced by vagotomy) Decreased blood glucose Decreased blood glucose Decreased blood glucose; effect enhanced by TPA (a protein kinase C activator) and blocked by polymyxin B or psychosine (protein kinase C blockers) No effect on the J4C-2DG uptake in the VMH Inhibited 80% of the warmresponsive units in the hypothalamus; excited 70% of the cold-responsive units Increased hot-plate latencies; no effect on blood glucose or insulin; no effect on body temperature Decreased plasma epinephrine and norepinephrine in VMH-lesioned animals; no effect on blood glucose Decreased plasma free fatty acids in normal fasted and diabetic animals Decreased nighttime and increased daytime food intake (Wistar rats) No effect on total daily food intake; no effect on insulin binding to various brain areas (Sprague-Dawley rats) No effect on food intake or plasma glucose in diabetic animals No effect on blood glucose or plasma insulin Increased blood glucose after 15 min Increased food intake; affected the neuronal activity in the LHA Inhibited the sympathetic nerve activity to brown adipose tissue in lean and obese Zucker rats; administration of insulin plus glucose potentiated the increase in activity observed with glucose alone Decreased nighttime food intake Decreased nighttime food intake

Reference 8 179 5 6

51 220

21

114,115

36

133

120

126

135 185 217

91

154 154

INSULIN IN T H E C E R E B R O S P I N A L F L U I D

251

TABLE 3 (CONTINUED) Administration Route

Amounts of Insulin

Rat

IIIV

Rat

UIV

7.5 and 10 mIU/day/7 days l0 mIU/day/7 days

Rat

IIIV

2 mIU/day/14 days

Rat

IIIV

Rat

IIIV

100 neonatal pancreatic islets 0.1 mlU

Rat

IIIV

100 nlU

Rat

IVV

5 IU/kg

Rat Rat

IC IC

0.1 IU 0.2 IU

Rat

IC

0.1 IU

Rat

IC

52-520 mIU

Cat

LCV

0. I-0.3 IU

Cat

IC

0.5 IU/kg

Dog

LCV

0.2 IU/kg

Dog

LCV

0.2 IU/kg

Dog

IUV

200 mlU/min

Dog Dog

IC IC

200 mlU/min plus glucose 200 mlU/min plus 2-DG 4 IU 20 IU

Dog

IC

5..-40 IU

Dog

IC

1-2 IU/kg

Dog

IC

16 IU

Dog

IC

13-16 IU

Species

Effect Decreased food intake and body weight Decreased food intake and body weight Decreased food intake in lean Zucker (Fa/fa) rats: no effect in obese Zucker (fa/fa) rats* Increased CSF insulin and decreased body weight after 7 and 14 days No effect on hepatic venous plasma glucose concentration Decreased hypothalamic TRH and increased plasma TRH and thyrotropin Increased the turnover rate of catecholamines in hypothalamus and medulla Increased brain glycogen Increased brain glycogen, glucose-6-phosphate and lactate No effect on brain tryptophan, serotonin and 5-HIAA Increased the activity of ornithine decarboxylase No effect on the absorption of glucose or a4-C-D-galactose from the cerebral ventricles Decreased CSF glucose, but increased blood glucose Increased insulin in the superior pancreaticoduodenal vein Increased insulin in the superior pancreaticoduodenal vein Increased plasma insulin; decreased plasma free fatty acids No change in plasma insulin, free fatty acids, or glucose Increased plasma insulin No change in blood glucose Decreased CSF and blood glucose Decreased CSF and blood glucose Slight decrease in blood glucose after 45 min Decreased CSF and blood glucose; in vagotomized animals only decreased CSF glucose Decreased blood glucose in normal and vagotomized animals

Reference 23 69 94

159

93 131

173

129 191

118

167 26

4 30 226 194,195

182 182 31 113 32

123

252

PLATA-SALAM,~N

TABLE 3 (CONTINUED)

Species

Administration Route

Dog

IC

Goat

Baboon

Subarachnoid (superfusion through cranial window) LCV

Baboon

CM

Amounts of Insulin 0.2 IU/kg

1 IU/min; rate = 2.0 ml/min

10 and 100 ~IU/kg/day/14 days 100 v.IU/kg/day

Effect

Reference

Increased plasma insulin; decreased plasma glucose. Both responses were attenuated in vagotomized animals Increased cortical cerebral glucose utilization by 8-15%

230

Decreased food intake and body weight Potentiated food intake suppression by CCK-8

227

147

68

Abbreviations: CM, cisterna magna; CSF, cerebrospinal fluid: IC, intracisternal; LCV, lateral cerebral ventricle; IIIV, third ventricle; IVV. fourth ventricle; LHA, lateral hypothalamic area; TPA, 12-O-tetradecanoylphorbol-13-acetate; TRH, thyrotropin-releasing hormone; VMH, ventromedial hypothalamus; 2-DG, 2-deoxy-D-glucose: 5-HIAA, 5-hydroxyindoleacetic acid. *A decrease in brain insulin binding has been reported in obese (fa/fa) Zucker and Wistar Kyoto (fa/fa) rats (66). tlnsulin can act as either hunger- or satiety-inducing signal depending on the amounts of insulin administered [see (154)]. endothelial cells (transcytosis) is mediated by a specific insulin receptor process (12-14, 29, 47, 48, 60, 71, 73, 96-98, 100, 103, 104, 141, 146). Physiological and biochemical studies suggest that insulin is transported in an intact form from brain capillaries into the pericapillary spaces and possibly into the brain parenchyma (60). It could be speculated that if insulin reaches the brain parenchyma, it may diffuse through the interstitial space and enter into the ventricular and subarachnoid CSF. The CSF/ plasma ratio for insulin indicates a selective transport into the CNS (140). The activity of the insulin transport system of the BBB seems to be proportional to the CSF/plasma insulin ratio (70). This ratio is high in developing animals (60,70), or in species with relatively large brains (dog, monkey, human) (233). 3) Indirect evidence suggests that blood-borne insulin may enter into the CSF through the choroid plexuses ( 1 l, 42, 139,234). Insulin may also enter into the CSF through other CVOs (77, 128, 141). It is suggested that insulin gains slow access to brain interstitial fluid in the CVOs and may be transported to contiguous brain sites (by simple diffusion) (43) or into CSF (by specific ependymal transport systems) (140). Immunoreactive insulin is localized in tanycytes and ependymal cells of the ventricular system in rodents (54, 55,139) and humans (27,56), and the ependymal processes of these cells extend to various hypothalamic nuclei (139). In addition, intracardial administration of labeled insulin results in specific binding localized to basal tanycyte processes (205, 207, 209). With this evidence it can be speculated that blood-borne insulin may have direct access to the CSF through tanycytes (156), and that ventricular ependymal cells may take up insulin from the CSF by a saturable nonspecific uptake mechanism (18). Other anatomical and physiological studies also show that peptides derived from the hypophyseal portal blood have direct access to the CSF through tanycytes (156). The specific binding of insulin to other glial cells (236) including astrocytes (3,33) might also represent an insulin distributing system and an uptake mechanism of CSF or blood insulin. The transport of insulin between the periphery and the CSF-brain may include other routes such as the intraaxonal anterograde and/or retrograde transport in the peripheral nerves (25). 4) Insulin can be transported in both directions between the peripheral blood and the brain-CSF through the BBB and CVOs.

It is also possible that some of the effects reported after the ICV administration of high amounts of insulin are related to a direct action on extracerebral receptors (Table 2 and 3). 5) Various studies indicate that CSF insulin responds slowly to acute changes in blood insulin (8, 30, 122, 232). It has been shown that: 1) basal levels of CSF insulin are correlated with plasma insulin (192); 2) fasting decreases CSF insulin in rats (187) and obese human subjects (138); and 3) increased blood insulin leads to a delayed rise of CSF insulin in rodents (185,186), dogs (232), baboons (68a), and humans (218,219). This evidence is compatible with the regulation of food intake and body weight proposed for insulin (46, 150, 152, 154, 202, 227, 229, 231, 233). It is important to note, however, that responses of CSF insulin during intravenous glucose infusion (186, 192, 219, 232) may depend on the state of energy balance. While plasma insulin increascd during glucose infusion in control and fasting conditions (192), CSF insulin increased only in the control condition (192). This evidence suggests a decreased transport of insulin from blood to the CSF during fasting (192) and/or a decreased release of insulin from an intracerebral source. Genetically obese Zucker rats have low CSF-to-plasma insulin ratio (189), also suggesting a decreased transport of insulin from blood to the CSF. This is also supported by the lack of a proportional increase of CSF insulin in obese Zucker rats peripherally infused with insulin for several days [(188) Table 2]. The decreased binding activity of insulin receptors in cerebral microvesselg may also contribute to the lower brain insulin content observed in diabetic animals (72). Several studies have not found a clear correlation between CSF and plasma insulin (76, 108, 162, 163). As above mentioned, methodological considerations have been implicated in these differences. FUTUREDIRECTIONS To understand the neurophysiological or neuropathophysiological significance of insulin in the CSF and the interaction between insulin and the CNS, the following aspects should be elucidated: 1) relationship between CSF and blood insulin concentrations during physiological (e.g., development, aging, nutritional sta-

INSULIN IN T H E C E R E B R O S P I N A L FLUID

253

tus, diurnal influences, variations o f metabolic factors such as glucose) and pathophysiological (e.g,, obesity, diabetes mellitus and other endocrinopathies) conditions; 2) distribution o f insulin in the C S F compartments (concentration gradients) and brain interstitial fluid; 3) influence o f CSF insulin in the brain insulin content and vice versa; 4) mechanism(s) o f biosynthesis, processing, storage and release o f insulin in the CNS; 5) mechanism(s) underlying the transcytosis process and implications o f alterations in the insulin-BBB and insulin-CVOs interactions; 6) mechanisms o f insulin inactivation in the C S F and brain which may include:

enzymes (oxidoreductase and proteinases) (57), dissociation from the receptors, concentrative uptake, and receptor-associated internalization, or a combination o f these mechanisms (117); 7) relationship between insulin and other chemical factors also present in the CSF such as insulin-like growth factors (137,193) and their binding proteins (168, 169, 199), as well as other neuropeptides (151); and 8) regulation o f insulin receptors in the CNS, and molecular events and second-third messengers following the interaction insulin-receptor.

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PLATA-SALAM/~I

59. 60. 61. 62. 63. 64.

65. 66. 67. 68. 68a

69.

70.

71. 72. 73.

74.

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Insulin in the cerebrospinal fluid.

The presence, distribution and specific localization of insulin and its receptors in the central nervous system (CNS) have been described in numerous ...
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