Table 2.
Intranasal insulin treatment outcomes.
| CNS function | Clinical subjects | Intranasal insulin | Phenotype | Treatment outcomes | Refs |
|---|---|---|---|---|---|
| Metabolism | Diabetics – fed | 1 or 2 doses (100 IU) | Glycemia | Lowered blood glucose in all patients. | [27] |
| Diabetics – fasted | Single dose (25 IU) | Rare occurrence of hypoglycemic shock via intranasal method. | |||
| Normal subjects | Single dose (20–60 IU) | Glycemia | Induced hypoglycemia. | [59] | |
| Insulin-dependent diabetics | Single dose | Improved postprandial hyperglycemia. | |||
| Healthy subjects | Single dose (0.5 IU/kg) | Glycemia | Reduced blood glucose concentrations with insulin-deoxycholate aerosol. | [60] | |
| Type 1 and 2 diabetics | |||||
| Normal subjects | Single dose (1 IU/kg) | Glycemia | Lowered fasting and postprandial glucose levels. | [61] | |
| Type 1 diabetic men and women | 3 months | Improved long-term glycemic control. | |||
| Non-obese type 2 diabetic men and women | Single dose (30 IU) | Glycemia | Hypoglycemic effect persisted for less than 2 h in the fasting state. Reduction in postprandial hyperglycemia persisted for 4 h. | [63] | |
| Type 1 diabetic men and women | 3 doses (up to 120 IU each) t.i.d. at meals | Glycemia | Controlled glycemia in half of patients with intranasal insulin when combined with daily ultralente insulin. | [62] | |
| Fasted normal men | Single dose (1 IU/kg) | Glycemia | Blood glucose concentration decreased at 45 min. | [64] | |
| Type 2 diabetics | Single dose (60 or 120 IU) | Glycemia | No hypoglycemia; effective at reducing post-prandial hyperglycemia. | [65] | |
| Type 2 diabetics with oral drug failure | 4 months (up to 240 IU/day, t.i.d.) | Glycemia | Similar diabetes control to conventional treatment with twice daily NPH insulin. | [66] | |
| Normal weight men or women | single dose (160 IU) | Glycemia | Increased plasma insulin and decreased plasma glucose. | [57] | |
| Increased fMRI activity in the hypothalamus correlated with increased HOMA-IR at 30 min post treatment. | |||||
| Decreased fMRI activity in the putamen, right insula and orbitofrontal cortex correlated with decreased HOMA-IR at 120 min post treatment. | |||||
| Type 2 diabetics | single dose (15 IU) | Glycemia | No improvement in post-prandial hyperglycemia. | [67] | |
| Insulin-dependent diabetics | 1 month (at mealtimes, various doses) | Glycemia | Metabolic control deteriorated compared to subcutaneous insulin therapy. | [68] | |
| Healthy subjects | 1.5 h (20 IU, every 15 min) | Glycemia | No effect on glycemia and insulin levels. | [69] | |
| Normal weight men | single dose (160 IU) | Glycemia | No effect on postprandial glucose concentrations. | [70] | |
| Normal weight men or women | single dose (160 IU) | Weight | Decreased food intake in men, not in women. | [72] | |
| Normal weight pre and post menopausal women | single dose (160 IU) | Weight | No effect on food intake. | [73] | |
| Obese men | 8 weeks (40 IU, q.i.d.) | Weight | No effect on weight or body fat. | [80] | |
| Normal weight women | single dose (160 IU) | Weight | Decreased appetite, food intake and rated palatability after postprandial insulin. | [75] | |
| Normal weight men | single dose (40 IU) | Weight | Increased brain ATP and phosphocreatine. | [76] | |
| Change in cerebral energy content correlated inversely with subsequent calorie intake. | |||||
| Normal weight men or women | single dose (160 IU) | Weight | Reduced food image-cued activity in the fusiform gyrus, hippocampus, and temporal superior and frontal middle cortex. | [77] | |
| No effect on nonfood image-cued brain activity. | |||||
| Normal weight women | single dose (160 IU) | Weight | Modulation of hypothalamus and orbitofrontal cortex activity by insulin. | [78] | |
| Correlation of prefrontal cortex and anterior cingulate cortex insulin response with BMI. | |||||
| Normal weight men or women | 8 weeks (40 IU, q.i.d.) | Weight | Reduced weight and body fat in men. | [74] | |
| No effect in women. | |||||
| Normal weight men or women | single dose (160 IU) | Lipolysis | Suppressed systemic FFA levels without affecting lipolytic proteins in subcutaneous adipose tissue. | [143] | |
| Normal weight men | single dose (160 IU) | Thermogenesis | Increased postprandial diet-induced thermogenesis. | [70] | |
| Lean and obese men | two days (160 IU per day) | Insulin sensitivity | Improved peripheral insulin sensitivity in lean but not obese men. | [71] | |
| Lean and type 2 diabetic men or women | 1 week (160 IU per day) | Hepatic fat and energy metabolism | Rapid improvement of hepatic energy metabolism without affecting hepatic insulin sensitivity in healthy humans, independent of peripheral insulinemia. Blunted response in patients with type 2 diabetes. | [144] | |
| Lean and obese or overweight men | single dose (160 IU) | Cerebral blood flow | Selectively impaired brain insulin action in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue. | [79] | |
| Memory | Amnestic MCI or early AD or healthy | single dose (20 IU or 40 IU) | Verbal memory | Facilitated recall on two measures of verbal memory in memory-impaired APOE-ɛ4- adults. These effects were stronger for memory-impaired APOE-ɛ4- subjects than for memory-impaired APOE-ɛ4+ subjects and normal adults. | [15] |
| Amnestic MCI or early AD | 3 weeks (20 IU) | Verbal memory | Enhanced verbal memory, selective attention, and functional status. | [123] | |
| Raised fasting plasma A beta 40/42 ratio. | |||||
| Amnestic MCI or AD or healthy subjects | 5 days (10, 20, 40, or 60 IU) | Verbal memory | Facilitated recall on two measures of verbal memory in memory-impaired APOE-ɛ4- adults. | [121] | |
| Differentially modulated plasma amyloid-β for memory-impaired subjects and normal controls, with effects that differed by APOE genotype. | |||||
| Healthy men | 8 weeks (40 IU, q.i.d.) | Declarative memory | Improved declarative memory. | [122] | |
| Healthy men | 8 weeks (40 IU, q.i.d.) | Declarative memory | Improved declarative memory and attention. | [119] | |
| Obese men | 8 weeks (40 IU, q.i.d.) | Declarative memory | Improved declarative memory. | [80] | |
| Amnestic MCI or mild to moderate AD | 4 months (20 or 40 IU) | Dementia | Improved delayed memory with 20 IU intranasal insulin. | [124] | |
| Testing | Preserved cognition and functional abilities with 20 and 40 IU insulin. | ||||
| Correlation between effects on memory and function with CSF Aβ42 and tau/Aβ42. | |||||
| APOE-ɛ4 carriers with mild-moderate AD | Single dose (40 IU) | Memory | No impact on cognition; serum insulin levels dropped post treatment, but peripheral glucose levels were unchanged. | [145] | |
| Healthy men | Single dose (40 IU) | Memory | Improved odor-cued reactivation of spatial memory. | [146] | |
| Normal weight men or women | Single dose (160 IU) | Working memory | Improved hippocampus-dependent memory and working memory in women, not men. | [72] | |
| Normal weight pre and post menopausal women | Single dose (160 IU) | Working memory | Enhanced prefrontal cortex-dependent working memory. | [73] | |
| MCI or mild to moderate AD | 3 weeks (20 or 40 IU) | Working memory | Improved memory composite (in APOE-ɛ4 carriers), verbal working memory and visuospatial working memory with 40 IU of insulin detemir. | [147] | |
| Non-diabetic and diabetic men and women | Single dose (40 IU) | Visio-spatial memory | Improved visiospatial memory acutely, correlated with regional vasoreactivity and cerebral vasodilatation. | [120] | |
| Older adults with type 2 diabetes | Single dose (40 IU) | Cognitive performance | Increased resting-state functional connectivity between the hippocampal regions and default mode network. | [148] | |
| Mood | Obese men | 8 weeks (40 IU, q.i.d.) | HPA axis | Improved mood and reduces HPA axis activity. | [80] |
| Healthy men | Single dose (40 IU) | HPA axis | Reduced saliva and plasma cortisol after experimental social stress. | [136] | |
| Healthy men | 8 weeks (40 IU, q.i.d.) | Mood | Enhanced mood and self-confidence, reduces anger. | [119] | |
| Bipolar disorder, euthymic | 8 weeks (40 IU, q.i.d.) | Executive function | Improved executive function, as measured by the Trail Making Test-Part B. | [137] | |
| No effect on other neurocognitive tests. |
AD, Alzheimer's disease; CNS, central nervous system; CSF, cerebrospinal fluid; FFA, free fatty acid; fMRI, functional magnetic resonance imaging; HOMA-IR, homeostasis model assessment-insulin resistance, HPA, hypothalamic-pituitary-adrenal; MCI, mild cognitive impairment; t.i.d., ter in die (three times a day); q.i.d., quarter in die (four times a day).