Intranasal insulin: from nose to brain.

BACKGROUND: Intranasal insulin has proven useful to control hyperglycemia in diabetics but its mechanism of action has not been well defined. We attempted to understand several aspects of human insulin metabolism by measurement of and interaction of insulin and its associated moieties in nasal mucus, saliva and blood plasma under various physiological and pathological conditions. METHODS: Insulin, insulin receptors, insulin-like growth factor 1 (IGF1) and insulin-like growth receptor 3 (IGFR3) were measured in nasal mucus, saliva and blood plasma in normal subjects, in thin and obese subjects and in diabetics under fasting and fed conditions. RESULTS: There are complex relationships among each of these moieties in each biological fluid. Insulin and its associated moieties are present in both nasal mucus and saliva. These moieties in nasal mucus and saliva report on physiological and pathological changes in glucose metabolism as do these moieties in plasma. Indeed, insulin and its associated moieties in nasal mucus may offer specific data on how insulin enters the brain and thereby play essential roles in control of insulin metabolism. INTERPRETATION: These data support the concept that insulin is synthesized not only in parotid glands but also in nasal serous glands. They also support the concept that insulin enters the brain following intranasal administration either 1) by direct entry through the cribriform plate, along the olfactory nerves and into brain parenchyma, 2) by entry through specific receptors in blood-brain barrier and thereby into the brain or 3) some combination of 1) and 2). Conversely, data also show that insulin introduced directly into the brain is secreted out of brain into the peripheral circulation. Data in this study demonstrate for the first time that insulin and its associated moieties are present not only in saliva but also in nasal mucus. How these complex relationships among nasal mucus, saliva and plasma occur are unclear but results demonstrate these relationships play separate yet interrelated roles in physiology and pathology of human insulin metabolism.

Inhaled insulin-intrapulmonary, intranasal, and other routes of administration: mechanisms of action.

BACKGROUND: After discovery of insulin as a hypoglycemic agent in 1921 various routes of administration to control blood glucose were attempted. These included subcutaneous, oral, rectal, sublingual, buccal, transdermal, vaginal, intramuscular, intrapulmonary and intranasal delivery systems. While each delivery system controlled hyperglycemia the subcutaneous route was given priority until 2006 when the Federal Drug Administration (FDA) approved the first commercially available pulmonary inhaled insulin. METHODS: A review of major publications dealing with intrapulmonary administration of insulin was made to understand the physiological basis for its use, its efficacy in controlling hyperglycemia, its side effects and a comparison of its efficacy with other delivery methods. RESULTS: The large surface area of the lung, its good vascularization, capacity for solute exchange and ultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin delivery. Large lung surface area ( approximately 75 m(2)) and thin alveolar epithelium ( approximately 0.1-0.5 microm) permit rapid drug absorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug delivery depends upon a complex of factors including size, shape, density, charge and pH of delivery entity, velocity of entry, quality of aerosol deposition, character of alveoli, binding characteristics of aerosol on the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studies were performed to optimize each of these factors using several delivery systems to enhance pulmonary absorption. Availability was about 80% of subcutaneous administration with peak activity within 40-60 min of administration. Intranasal insulin delivery faces a smaller surface area ( approximately 180 cm(2)) with quite different absorption characteristics in nasal epithelium and its associated vasculature. Absorption depends upon many factors including composition and character of nasal mucus. Absorption of intranasal insulin resulted in a faster absorption time course than with subcutaneous insulin. INTERPRETATION: After many studies the FDA approved Pfizer's product, Exubera, for intrapulmonary insulin delivery. While the system was effective its expense and putative side effects caused the drug company to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies to use intrapulmonary insulin delivery are presently being made as well as some minor attempts to use intranasal delivery systems.

cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age.

PURPOSE: To evaluate the presence and concentration of cAMP and cGMP in human nasal mucus in normal volunteers, to relate these findings to age and gender, and to compare normal levels with those in patients with taste and smell dysfunction. METHODS: Nasal mucus was collected over one to four days in 66 normal subjects and 203 patients with smell loss (hyposmia). Samples were centrifuged at 20,000 rpm, the supernatant removed and analyzed for cAMP and cGMP by using a 96 plate technique with a specific spectrophotometric colorimetric ELISA assay. RESULTS: Both cAMP and cGMP were present in human nasal mucus with both cAMP and cGMP significantly higher in normal women than in normal men [men vs. women; cAMP, 0.23+/-0.002 vs. 0.34+/-0.05 (P < 0.05); cGMP, 0.28+/-0.03 vs. 0.63+/-0.12 (P < 0.01)]. Both cAMP and cGMP changed with age; both moieties increased in a U shaped, parabolic pattern reaching a peak at age 41-50 with cAMP diminishing thereafter and then increasing to its highest level over age 70. Both cAMP and cGMP were lower in patients with taste and smell dysfunction than in normal subjects [normals vs. patients; cAMP, 0.31+/-0.05 vs. 0.15+/-0.02 (P < 0.01); cGMP, 0.56+/-0.07 vs. 0.025+/-0.02 (P < 0.001)] suggesting a relationship to olfactory pathology. CONCLUSIONS: This is the first definitive study to demonstrate the presence of these cyclic nucleotides in nasal mucus and the first to reveal decreased levels in patients with impaired taste and smell function. Since olfactory receptor sensitivity decreases with age increased nasal mucus cAMP over age 70 may appear incongruous but suggests one role of cAMP in olfactory function may relate to feedback mechanism(s) whereby its increase over age 70 yr reflects a physiological attempt to enhance diminishing lfactory function through growth and development of olfactory receptor activity.

cAMP and cGMP in nasal mucus related to severity of smell loss in patients with smell dysfunction.

PURPOSE: To evaluate nasal mucus levels of cAMP and cGMP in patients with taste and smell dysfunction with respect to severity of their smell loss. METHODS: cAMP and cGMP were measured in nasal mucus using a sensitive spectrophotometric 96 plate ELISA technique. Smell loss was measured in patients with taste and smell dysfunction by standardized psychophysical measurements of olfactory function and classified by severity of loss into four types from most severe to least severe such that anosmia > Type I hyposmia > Type II hyposmia > Type III hyposmia. Measurements of nasal mucus cyclic nucleotides and smell loss were made independently. RESULTS: As smell loss severity increased stepwise cAMP and cGMP levels decreased stepwise [cAMP, cGMP (in pmol/ml); anosmia - 0.004, 0.008: Type I hyposmia - 0.12+/-0.03, 0.10+/-0.03: Type II hyposmia - 0.15+/-0.02, 0.16+/-0.01: Type III hyposmia - 0.23+/-0.05, 0.20+/-0.15]. CONCLUSIONS: These results confirm the association of biochemical changes in cyclic nucleotides with systematic losses of smell acuity. These results confirm the usefulness of the psychophysical methods we defined to determine the systematic classification of smell loss severity. These changes can form the basis for the biochemical definition of smell loss among some patients with smell loss as well as for their therapy.

Deficient dietary intake of vitamin E in patients with taste and smell dysfunctions: is vitamin E a cofactor in taste bud and olfactory epithelium apoptosis and in stem cell maturation and development?

OBJECTIVES: We reviewed dietary intake of several nutrients in a large group of patients with taste and smell dysfunction, compared intake of these nutrients with standard values, and recognized that intake of vitamin E was significantly less than that of most other nutrients. Based on this observation we attempted to develop an hypothesis of the possible role vitamin E might play in these sensory disorders. METHODS: Vitamin E intake was measured in 250 patients with taste and smell dysfunctions. RESULTS: Intake of the vitamin was 3.2 +/- 0.2 mg/d (mean +/- standard error of the mean), or 36 +/- 2% of the recommended daily allowance, an intake significantly below that considered adequate. This diminished intake occurred with normal intake of total calories; protein; fat; carbohydrate; several vitamins, including thiamin, niacin, and pyridoxine; and the trace metals zinc, copper, and iron. CONCLUSIONS: Although specific relations between vitamin E intake and smell and taste dysfunctions are unclear, the non-antioxidant roles of vitamin E indicate that it is a factor in apoptosis, cellular signaling, and growth of various cell lines, suggesting that this vitamin may play a role in growth and development of stem cells in taste buds and olfactory epithelium.

Lateralization of brain activation to imagination and smell of odors using functional magnetic resonance imaging (fMRI): left hemispheric localization of pleasant and right hemispheric localization of unpleasant odors.

PURPOSE: Our goal was to use functional MRI (fMRI) of brain to reveal activation in each cerebral hemisphere in response to imagination and smell of odors. METHOD: FMRI brain scans were obtained in 24 normal subjects using multislice fast low angle shot (FLASH) MRI in response to imagination of banana and peppermint odors and in response to smell of corresponding odors of amyl acetate and menthone, respectively, and of pyridine. Three coronal sections selected from anterior to posterior brain regions were used. Similar studies were obtained in two patients with hyposmia using FLASH MRI and in one patient with hyposmia using echo planar imaging (EPI) both before and after theophylline treatment that returned smell function to or toward normal in each patient and in two patients with birhinal phantosmia (persistent foul odor) and global phantogeusia (persistent foul taste) with FLASH and EPI fMRI before and after treatment with neuroleptic drugs that inhibited their phantosmia and phantogeusia. Activation images were derived using correlation analysis. Ratios of hemispheric areas of brain activation to total hemispheric brain areas were calculated for FLASH fMRI, and numerical counts of pixel clusters in each hemisphere were made for EPI studies. Total pixel cluster counts in localized regions of each hemispheric section were also obtained. RESULTS: In normal subjects, activation generally occurred in left (L) > right (R) brain hemisphere in response to banana and peppermint odor imagination and to smell of corresponding odors of amyl acetate and menthone. Whereas there were no overall hemispheric differences for pyridine odor, activation in men was R > L hemisphere. Although absolute activation in both L and R hemispheres in response to banana odor imagination and amyl acetate smell was men > women, the ratio of L to R activation was women > men. In hyposmic patients studied by FLASH fMRI, activation to banana odor imagination and amyl acetate smell was L > R hemisphere both before and after theophylline treatment. In the hyposmic patient studied with EPI before theophylline treatment, activation to banana and peppermint odor imagination and to amyl acetate, menthone, and pyridine smell was R > L hemisphere; after theophylline treatment restored normal smell function, activation shifted completely with banana and peppermint odor imagination and amyl acetate and menthone smell to L > R hemisphere, consistent with responses in normal subjects. However, this shift also occurred for pyridine smell, which is opposite to responses in normal control subjects. In patients with phantosmia and phantogeusia, activation to phantosmia and phantogeusia before treatment was R > L hemisphere; after treatment inhibited phantosmia and phantogeusia, activation shifted with a slight L > R hemispheric lateralization. Localization of all lateralized responses indicated that anterior frontal and temporal cortices were brain regions most involved with imagination and smell of odors and with phantosmia and phantogeusia presence. CONCLUSION: Imagination and smell of odors perceived as pleasant generally activated the dominant or L > R brain hemisphere. Smell of odors perceived as unpleasant and unpleasant phantosmia and phantogeusia generally activated the contralateral or R > L brain hemisphere. With remission of phantosmia and phantogeusia, hemispheric activation was not only inhibited, but also there was a slight shift to L > R hemispheric predominance. Predominant L > R hemispheric differences in brain activation in normal subjects occurred in the order amyl acetate > menthone > pyridine, consistent with the hypothesis that pleasant odors are more appreciated in L hemisphere and unpleasant odors more in R hemisphere. Anterior frontal and temporal cortex regions previously found activated by imagination and smell of odors and phantosmia and phantogeusia perception accounted for most hemispheric differences.