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

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

Detailed Description
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Somatostatin
* Other: Dextrose
* Drug: Insulin
* Other: Intralipid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Elevation of fasting FFA and Glucose<br>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<br>* Somatostatin will be used to inhibit endogenous insulin secretion on either study day in both arms of the study<br>* Other names: pancreatic clamp;Other: Dextrose<br>* intravenous glucose will be used to raise fasting glucose in people with NFG / NGT<br>* Other names: Elevation of glucose;Other: Intralipid<br>* intravenous intralipid (Fat Emulsion) will be used to raise fasting FFA in people with NFG / NGT<br>* Other names: Elevation of FFA;|
| Other: Lowering of fasting FFA and glucose<br>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<br>* Somatostatin will be used to inhibit endogenous insulin secretion on either study day in both arms of the study<br>* Other names: pancreatic clamp;Drug: Insulin<br>* insulin will be used to lower fasting FFA and glucose in people with IFG / IGT<br>* Other names: glucose clamp;|

What is the study measuring?
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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 |