Effects of Intranasal Insulin Administration on Tissue Specific Insulin Sensitivity

NCT02933645 | Completed

• 2 other identifiers: T210/20152015-005392-24
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Insulin Resistance

Keywords

Insulin; Intranasal; Glucose/metabolism; Glucose homeostasis

Outcome Measures

Primary Outcomes (1)

• Skeletal muscle glucose uptake

  Change in skeletal muscle insulin stimulated glucose uptake (μmol/min/kg) after insulin versus placebo nasal spray administration.

  Data is collected during 100 min PET scan started 40 min after spray administration.

Secondary Outcomes (2)

• Endogenous glucose production

  Data is collected during 100 min PET scan started 40 min after spray administration.

• Liver glucose uptake

  Data is collected during 100 min PET scan started 40 min after spray administration.

Study Arms (2)

Insulin nasal spray

ACTIVE COMPARATOR

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain fast-acting human insulin Actrapid (Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) over 15 minutes. 30 min before spray administration a hyperinsulinemic euglycemic clamp will be started and continued for 170 minutes. 40 min after spray administration \[18F\]-FDG PET-CT scan lasting 100 min is started.

Drug: Actrapid; Radiation: [18F]-FDG PET-CT; Drug: Hyperinsulinemic euglycemic clamp

Placebo nasal spray

PLACEBO COMPARATOR

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain Insulin Diluting Medium for Novorapid and Levemir (Novo Nordisk A/S, Bagsvaerd,Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd,Denmark) over 15 min. 30 min before spray administration a hyperinsulinemic euglycemic clamp will be started and continued for 170 minutes. 40 min after spray administration \[18F\]-FDG PET-CT scan lasting 100 min is started.

Drug: Placebo; Radiation: [18F]-FDG PET-CT; Drug: Hyperinsulinemic euglycemic clamp

Interventions

Actrapid DRUG

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays or 160 IU of fast-acting human insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray.

Also known as: ATC-code A10AB01

Insulin nasal spray

Placebo DRUG

Subjects administer 2 intranasal sprays into each nostril every minute for 4 minutes, a total of 16 sprays. Sprays contain Insulin Diluting Medium for Novorapid and Levemir (Novo Nordisk A/S, Bagsvaerd, Denmark). The glass spray flasks are produced by AeroPump GmBH, Germany and give 0,1 ml of fluid per spray. To account for the small amount of insulin absorbed into circulation after the insulin nasal sprays, on the placebo day subjects will be administered 2.5 mU/kg of additional intravenous insulin (Actrapid, Novo Nordisk A/S, Bagsvaerd, Denmark) over 15 minutes.

Also known as: Insulin Diluting Medium for Novorapid and Levemir

Placebo nasal spray

[18F]-FDG PET-CT RADIATION

All subjects will undergo two positron emission tomography (PET) studies. On both visits they are injected with 185 MBq \[18F\]-fluorodeoxyglucose and scanned with a combined PET and computed tomography scanner.

Also known as: Tissue specific insulin sensitivity measurement

Insulin nasal spray; Placebo nasal spray

Hyperinsulinemic euglycemic clamp DRUG

All subjects will undergo two hyperinsulinemic euglycemic clamp studies. The insulin infusion will be administered intravenously at a steady rate of 0.25 mU/kg/min for approximately 170 minutes. Glucose will be administered intravenously as a 200 mg/ml fluid to at varying rate to maintain euglycemia.

Also known as: Whole-body insulin sensitivity measurement

Insulin nasal spray; Placebo nasal spray

Eligibility Criteria

• Age: 20 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI 18,5-25 kg/m2
• Fasting plasma glucose less than 6.1 mmol/l
• Normal 2-hour oral glucose tolerance test (OGTT)

You may not qualify if:

• Any chronic disease or medication that could affect glucose metabolism
• History of anorexia nervosa or bulimia
• Smoking of tobacco, taking of snuffs, or use of narcotics
• Abusive use of alcohol
• Any other condition that in the opinion of the investigator could create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results

Sponsors & Collaborators

• Turku University Hospital: lead
• University Hospital Tuebingen: collaborator

Study Sites (1)

Turku PET Centre

Turku, 20520, Finland

Location

Related Publications (12)

• 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.

  PMID: 25028522 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.

  PMID: 26460339 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.

  PMID: 11992114 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.

  PMID: 382871 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.

  PMID: 4055928 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.

  PMID: 11052968 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.

  PMID: 9115064 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.

  PMID: 17258736 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.

  PMID: 11793018 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.

  PMID: 23334481 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.

  PMID: 14499160 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.

  PMID: 16741312 BACKGROUND

MeSH Terms

Conditions

Insulin Resistance

Interventions

Insulin; Insulin Aspart; Insulin Detemir

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Insulin, Short-Acting; Insulin, Long-Acting

Study Officials

• Pirjo Nuutila, MD,PhD

  Turku University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 11, 2016
• First Posted: October 14, 2016
• Study Start: April 1, 2016
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: January 26, 2018

Record last verified: 2018-01

Locations

FI (1)