Effects of Intranasal Insulin Administration on Tissue Specific Insulin Sensitivity

Summary

Recent research has suggested that intranasally administered insulin can reach the brain quickly without passing through circulation and evoke increased insulin sensitivity and tissue glucose consumption during insulin stimulation (low-dose hyperinsulinemic, euglycemic clamp). It is still not known what mechanism causes these changes or what tissues are involved in this. In this study, the changes in tissue-specific insulin sensitivity and glucose uptake will be investigated by using glucose-analogue radiotracer (\[18F\]-fluorodeoxyglucose) with positron emission tomography (PET) imaging during insulin stimulation. Ten healthy males are studied, each receiving nasal sprays containing insulin or placebo in a randomized order on two separate days. After spray administration, glucose uptake in skeletal muscle, liver, subcutaneous and visceral adipose tissue, myocardium, intestines, brown adipose tissue and brain assessed by PET imaging and glucose uptake in these tissues is analyzed. Endogenous glucose production is calculated facilitating the measurements glucose and radiotracer uptake in tissues and tracer loss into urine. As skeletal muscle consumes most of the glucose available, it is likely that administration of insulin sprays will result in an increased uptake in this tissue. Some increase in glucose uptake might also be seen in other tissue types after insulin spray versus placebo spray administration.

Timeline

Start

2016-04

Primary completion

2016-12

Completion

2016-12

Publications

• Background Heni M, Wagner R, Kullmann S, Veit R, Mat Husin H, Linder K, Benkendorff C, Peter A, Stefan N, Haring HU, Preissl H, Fritsche A. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes. 2014 Dec;63(12):4083-8. doi: 10.2337/db14-0477. Epub 2014 Jul 15.
• Background Heni M, Kullmann S, Preissl H, Fritsche A, Haring HU. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol. 2015 Dec;11(12):701-11. doi: 10.1038/nrendo.2015.173. Epub 2015 Oct 13.
• Background Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002 Jun;5(6):514-6. doi: 10.1038/nn849. No abstract available.
• Background DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23. doi: 10.1152/ajpendo.1979.237.3.E214.
• Background Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab. 1985 Dec;5(4):584-90. doi: 10.1038/jcbfm.1985.87.
• Background Peltoniemi P, Lonnroth P, Laine H, Oikonen V, Tolvanen T, Gronroos T, Strindberg L, Knuuti J, Nuutila P. Lumped constant for [(18)F]fluorodeoxyglucose in skeletal muscles of obese and nonobese humans. Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1122-30. doi: 10.1152/ajpendo.2000.279.5.E1122.
• Background Botker HE, Bottcher M, Schmitz O, Gee A, Hansen SB, Cold GE, Nielsen TT, Gjedde A. Glucose uptake and lumped constant variability in normal human hearts determined with [18F]fluorodeoxyglucose. J Nucl Cardiol. 1997 Mar-Apr;4(2 Pt 1):125-32. doi: 10.1016/s1071-3581(97)90061-1.
• Background Iozzo P, Jarvisalo MJ, Kiss J, Borra R, Naum GA, Viljanen A, Viljanen T, Gastaldelli A, Buzzigoli E, Guiducci L, Barsotti E, Savunen T, Knuuti J, Haaparanta-Solin M, Ferrannini E, Nuutila P. Quantification of liver glucose metabolism by positron emission tomography: validation study in pigs. Gastroenterology. 2007 Feb;132(2):531-42. doi: 10.1053/j.gastro.2006.12.040. Epub 2006 Dec 21.
• Background Virtanen KA, Peltoniemi P, Marjamaki P, Asola M, Strindberg L, Parkkola R, Huupponen R, Knuuti J, Lonnroth P, Nuutila P. Human adipose tissue glucose uptake determined using [(18)F]-fluoro-deoxy-glucose ([(18)F]FDG) and PET in combination with microdialysis. Diabetologia. 2001 Dec;44(12):2171-9. doi: 10.1007/s001250100026.
• Background Honka H, Makinen J, Hannukainen JC, Tarkia M, Oikonen V, Teras M, Fagerholm V, Ishizu T, Saraste A, Stark C, Vahasilta T, Salminen P, Kirjavainen A, Soinio M, Gastaldelli A, Knuuti J, Iozzo P, Nuutila P. Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity. Diabetologia. 2013 Apr;56(4):893-900. doi: 10.1007/s00125-012-2825-5. Epub 2013 Jan 20.
• Background Wu HM, Bergsneider M, Glenn TC, Yeh E, Hovda DA, Phelps ME, Huang SC. Measurement of the global lumped constant for 2-deoxy-2-[18F]fluoro-D-glucose in normal human brain using [15O]water and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography imaging. A method with validation based on multiple methodologies. Mol Imaging Biol. 2003 Jan-Feb;5(1):32-41. doi: 10.1016/s1536-1632(02)00122-1.
• Background Iozzo P, Gastaldelli A, Jarvisalo MJ, Kiss J, Borra R, Buzzigoli E, Viljanen A, Naum G, Viljanen T, Oikonen V, Knuuti J, Savunen T, Salvadori PA, Ferrannini E, Nuutila P. 18F-FDG assessment of glucose disposal and production rates during fasting and insulin stimulation: a validation study. J Nucl Med. 2006 Jun;47(6):1016-22.

Drugs

Indications

No indication recorded.