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NCT Number: NCT02669524

Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes

In patients with type 2 diabetes, the incretin effect is markedly reduced contributing to the relative insulin deficiency that characterizes these patients. This defect is believed to be due to a decreased effect of GLP-1 and an almost ceased effect of GIP. Nevertheless, the impact of the defect on glucose tolerance is not fully understood. The so-called gastrointestinal-mediated glucose disposal (GIGD) is a measure of glucose handling, which includes the incretin effect, but also other factors affecting glucose disposal (e.g. glucagon secretion). Interestingly, patients with type 2 diabetes exhibit elevated plasma glucagon levels in the fasting state, and glucagon concentrations fail to decrease appropriately and may even increase in response to ingestion of glucose and show exaggerated increases after a mixed meal. With the current project the investigators wish to elucidate how this paradoxical glucagon response observed in patients with type 2 diabetes affects the GIGD, the incretin effect and postprandial glucose excursions.

Ten patients with type 2 diabetes and 10 healthy matched control subjects will be enrolled in this randomised, placebo-controlled, double-blinded study. The aim is to examine the effect of a glucagon receptor antagonist (GRA) on gastrointestinal-mediated glucose disposal (GIGD), incretin effect and postprandial glucose excursions in patients with type 2 diabetes and healthy controls. Participants will attend two oral glucose tolerance tests (OGTT), two isoglycaemic iv glucose infusion (IIGI) and two standardised liquid meals.

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Key information

Conditions

Type 2 Diabetes Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

35 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Center for Diabetes Research, Gentofte Hospital, Copenhagen University

Hellerup, DK-2900, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Patients with type 2 diabetes

  • Caucasians above 35 years of age with diet or metformin treated type 2 diabetes for at least 3 month (diagnosed according to the criteria of the World Health Organization (WHO)
  • Normal haemoglobin
  • Informed consent

Healthy subjects

  • Normal fasting plasma glucose (FPG) <6.1 mmol/l and HbA1c <42 mmol/mol (6.0%)
  • Normal haemoglobin
  • Age above 35 years
  • Informed consent

Exclusion criteria

Patients with type 2 diabetes

  • Inflammatory bowel disease
  • Intestinal resections
  • Nephropathy (serum creatinine above normal range and/or albuminuria)
  • Liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2×normal values)
  • Treatment with medicine that cannot be paused for 12 hours
  • Pregnancy and/or breastfeeding
  • Family history of pancreatic islet tumours
  • Age above 80 years

Healthy subjects

  • Diabetes or prediabetes with reduced glucose tolerance: FPG >6.0 mmol/l and/or HbA1c >42 mmol/mol
  • First degree relatives with type 2 diabetes
  • Inflammatory bowel disease
  • Intestinal resections
  • Treatment with medicine that cannot be paused for 12 hours
  • Pregnancy and/or breastfeeding
  • Age above 80 years

Treatment and study plan

LY2409021

Drug

LY2409021 placebo

Drug

OGTT

Procedure

IIGI

Procedure

Standardised liquid meal

Procedure

Primary outcomes

  1. Differences in GIGD (%)

    Time frame: Comparison between experimental days with and without the glucagon receptor antagonist . The glucose disposal at time 240 minutes will be used.

    GIGD = Gastrointestinal glucose disposal. GIGD (%) = 100% × (glucoseOGTT-glucoseIIGI)/glucoseOGTT.

  2. Difference in postprandial glucose excursions

    Time frame: Area under the curve (AUC) time frame: 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 105, 120, 150, 180, 210, 240 minutes. Comparison between experimental days with and without the glucagon receptor antagonist.

    Difference in postprandial glucose excursions (measured as incremental (baseline substracted) area under the curve (AUC) values).

Secondary outcomes

  1. Incretin effect

    Time frame: Insulin AUC time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes. Comparison between experimental days with and without the glucagon receptor antagonist

    The incretin effect (100% × [β-cell secretory response to oral glucose tolerance test - intravenous β-cell secretory response]/β-cell secretory response to oral glucose tolerance test)

  2. Endogenous glucose production

    Time frame: Plasma concentration of 6,6^2 H2-glucose and U-13C^6-glucose at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.

    Glucose rate of appearance will be calculated by the non-steady state equation using double tracer technique.

  3. Lipolysis

    Time frame: Plasma concentration of 1,1,2,3,3-^2-H5 - glycerol measured at times: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.

    Glycerol disappearance will be calculated by the non-steady state equation using double tracer technique.

  4. Serum/plasma concentrations of insulin, C-peptide, glucagon, GIP and GLP-1.

    Time frame: Time frame: 0,10, 20, 30, 50, 60, 70, 90, 105, 120, 150, 240 minutes.

    Insulin, C-peptide, glucagon, GIP and GLP-1 serum/plasma concentrations will be measured in pM.

  5. Appetite

    Time frame: VAS scales will be handed out at time 0, 30, 60, 90, 120, 150, 180 and 240 minutes.

    Appetite will be evaluated with a visual analogue scale (VAS).

  6. Energy intake (kcal/kJ)

    Time frame: At time 240 to 270, the participants will eat an ad libitum meal. Comparison between experimental days with and without the glucagon receptor antagonist

    At the end of the clamp experiment food intake will be examined with an ad libitum meal. The weight of the food will be measured i grams and calculated to the energy intake in kcal/kJ.

  7. Changes in blood pressure (mmHg)

    Time frame: Measured at time 0 and time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist

  8. Changes in pulse rate (beat per minute)

    Time frame: Measured at time 0 and at time 210 minutes. Comparison between experimental days with and without the glucagon receptor antagonist

  9. Differences in gastric emptying

    Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes

    Measurement of p-paracetamol. Measurement of time to peak and incremental area under the curve (iAUC)

  10. Free fatty acids

    Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes

    serum values of free fatty acids

  11. Fibroblast growth factor-21

    Time frame: -30,-15, 0, 10, 20, 30, 50, 70, 90, 105, 120, 150, 240 minutes

    plasma values of FGF-21

Sponsors and collaborators

Lead sponsor

University Hospital, Gentofte, Copenhagen

Other

Collaborators

  • Eli Lilly and Company

Registry information

Official study title

Dissection of the Gastrointestinal-mediated Glucose Disposal and Incretin Defect in Patients With Type 2 Diabetes - the Role of Glucagon

Important dates

Study start
2015
Primary completion
2016
Study completion
2016
First posted
Feb 1, 2016
Registry last updated
Oct 25, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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