Effect of Fasting Free Fatty Acids and Fasting Glucose on 1st and 2nd Phase Insulin Secretion

Researchers are trying to determine how changes in fasting glucose and free fatty acids (products released from fat) affect insulin secretion.

Study Overview

• Status: Withdrawn
• Conditions: Healthy
• Intervention / Treatment: Drug: Somatostatin; Other: Dextrose; Other: Intralipid; Drug: Insulin

Detailed Description

Non-invasive measurement of β-cell health is a long-hoped for tool in diabetes research. The observation that Type 2 Diabetes Mellitus (T2DM), and acute insulin resistance increase proinsulin concentrations led to the suggestion that a proinsulin/insulin ratio is a marker of β-cell integrity. However, proinsulin has a longer half-life (20-30min) than insulin (5min) and, unlike insulin, is not extracted by the liver. This limitation can only be overcome by direct and simultaneous measurement of insulin and proinsulin secretion. This experiment will measure in vivo proinsulin clearance so that proinsulin secretion can be calculated in people with differing degrees of glucose tolerance. It is also notable that subgroups of prediabetes differ in their fasting glucose and free fatty acid (FFA) concentrations. Whether short-term alteration of fasting glucose and FFA can alter subsequent prandial glucose metabolism is unknown. The loss of 1st phase insulin secretion(thought to represent release of pre-formed insulin granules) in T2DM can be partly restored by improved glycemic control although 2nd phase insulin secretion (thought to represent de novo synthesis of insulin) is unchanged. This experiment we will ascertain if changes in fasting FFA and glucose alter 1st and 2nd phase insulin secretion in people without diabetes.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Weight-stable, non-diabetic subjects from Biobank participants at Mayo Clinic, Rochester

Exclusion Criteria

• Age < 25 or > 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose).
• HbA1c ≥ 6.5%
• Use of glucose-lowering agents.
• For female subjects: positive pregnancy test at the time of enrollment or study
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Hormone replacement therapy >0.625 mg premarin daily

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Elevation of fasting FFA and Glucose; People with normal fasting glucose and normal fasting FFA (normal fasting glucose / normal glucose tolerance - NFG / NGT) will be studied on 2 occasions. On one occasion they will receive saline overnight and on the other they will receive intralipid and dextrose to raise fasting glucose and fasting FFA. Subsequently (on either study day) they will undergo a hyperglycemic clamp for 2 hours. After this somatostatin will be infused acutely to inhibit endogenous insulin secretion and observe clearance of beta-cell polypeptides.	Drug: Somatostatin; Somatostatin will be used to inhibit endogenous insulin secretion on either study day in both arms of the study; Other Names: pancreatic clamp; Other: Dextrose; intravenous glucose will be used to raise fasting glucose in people with NFG / NGT; Other Names: Elevation of glucose; Other: Intralipid; intravenous intralipid (Fat Emulsion) will be used to raise fasting FFA in people with NFG / NGT; Other Names: Elevation of FFA
Other: Lowering of fasting FFA and glucose; People with elevated fasting glucose and elevated fasting FFA (Impaired fasting glucose / impaired glucose tolerance - IFG / IGT) will be studied on 2 occasions. On one occasion they will receive saline overnight and on the other they will receive insulin to lower fasting glucose and fasting FFA. Subsequently (on either study day) they will undergo a hyperglycemic clamp for 2 hours. After this somatostatin will be infused acutely to inhibit endogenous insulin secretion and observe clearance of beta-cell polypeptides.	Drug: Somatostatin; Somatostatin will be used to inhibit endogenous insulin secretion on either study day in both arms of the study; Other Names: pancreatic clamp; Drug: Insulin; insulin will be used to lower fasting FFA and glucose in people with IFG / IGT; Other Names: glucose clamp

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First phase of Insulin secretion in response to manipulation of fasting FFA and glucose	1st phase of insulin secretion (Phi 1) - physiologic parameter	First 120 minutes of study
Second phase of Insulin secretion in response to manipulation of fasting FFA and glucose	2nd phase of insulin secretion (Phi 2) - physiologic parameter	First 120 minutes of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proinsulin secretion in response to manipulation of fasting FFA and glucose	proinsulin secretion - physiologic parameter	2nd 120 minutes of the study
proinsulin clearance in response to manipulation of fasting FFA and glucose	proinsulin clearance - physiologic parameter	2nd 120 minutes of the study

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: June 24, 2019
• First Submitted That Met QC Criteria: June 25, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): September 9, 2022
• Last Update Submitted That Met QC Criteria: September 8, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion; Somatostatin
• Other Study ID Numbers: 19-003325; R01DK078646 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No