NCT02971202

Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)

A Novel Cross-sectional Analysis of Insulin Sensitivity Among Adolescents and Young Adults With Type 1 Diabetes, MODY2, and Normal Controls: the Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 33 (actual)
• Sponsor: Vanderbilt University · Academic / Other
• Sex: All
• Age: 13 Years – 51 Years
• Healthy volunteers: Accepted

Summary

The purpose of this study is to determine the key factors influencing insulin sensitivity in type 1 diabetes (T1DM) and maturity onset diabetes of the young, type 2 (MODY2). Our study tests the hypothesis that decreased insulin sensitivity is primarily driven by chronically elevated insulin levels in the blood rather than chronic elevations in blood sugar.

Detailed description

This research will determine whether insulin resistance (IR) in T1DM is predominantly an effect of chronic hyperglycemia, as is commonly accepted, or a consequence of iatrogenic hyperinsulinemia in the peripheral circulation, as alternatively hypothesized. IR is a consistent but under-recognized finding in T1DM. Despite its independent contribution to micro- and macrovascular disease, its underlying cause has not been established nor have strategies to mitigate it been developed. This research will also characterize IR in maturity onset diabetes of the young, type 2 (MODY2), a population for whom IR has been inadequately studied to date. Insulin therapy in T1DM attempts to achieve euglycemia but does so in an "unphysiologic" way, by delivering insulin into the subcutaneous tissue as compared to physiologic delivery directly into the hepatic portal circulation. Although life-saving, peripheral insulin delivery in T1DM results in a loss of the normal insulin distribution; the physiologic state maintains insulin at 3-fold higher concentrations in the portal circulation compared with the peripheral circulation. IR in T1DM could therefore occur in response to peripheral hyperinsulinemia, a mechanism that would protect against hypoglycemia and ensure adequate glucose delivery to the central nervous system. MODY2 is a condition that results a mutation in the gene encoding glucokinase (GCK), which in turn causes a defect in β-cell sensitivity to glucose due to reduced glucose phosphorylation. This effectively raises the "set point" for insulin secretion in response to increased glycemia. Because MODY2 patients retain pancreatic insulin secretion, they usually require no insulin therapy and have a normal insulin distribution between the portal and peripheral circulations. We therefore hypothesize that IR in T1DM 1) is a homeostatic response to increased peripheral insulin concentrations resulting from peripheral insulin delivery and not significantly attributable to hyperglycemia and 2) results primarily from peripheral tissue IR (especially muscle) and not primarily from hepatic IR. Further, we anticipate that patients with MODY2, a population that has hyperglycemia without hyperinsulinemia, will have insulin sensitivity similar to that of otherwise healthy, nondiabetic individuals. To test this hypothesis, the hyperinsulinemic, euglycemic clamp will be used to assess IR in a cross-sectional study of 3 groups of subjects: 1. non-diabetic control subjects, 2. patients with well controlled T1DM, and 3. patients with MODY2 Key metabolic differences between these 3 groups will enable us to parse out the relative contributions of peripheral hyperinsulinemia vs. hyperglycemia to IR in T1DM and MODY2. Further, the proposed research will provide information on whether novel therapeutic strategies to restore the normal portal to peripheral insulin distribution can normalize insulin sensitivity (e.g. hepatopreferential insulin analogs, intraperitoneal insulin delivery).

Conditions

• Type 1 Diabetes Mellitus
• Maturity-Onset Diabetes of the Young, Type 2
• MODY2
• Insulin Resistance

Interventions

Type	Name	Description
DRUG	Hyperinsulinemic, euglycemic clamp	Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study: * insulin (12 mU/m\^2/min \[3x basal\] for 150 minutes, then 40 mU/m\^2/min \[10x basal\] for 180 minutes) * glucagon (0.65 ng/kg/min \[1x basal\] for 330 minutes) * somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
DRUG	20% dextrose	A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Timeline

• Start date: 2016-12-01
• Primary completion: 2019-02-01
• Completion: 2019-02-01
• First posted: 2016-11-22
• Last updated: 2019-08-01
• Results posted: 2019-08-01

Locations

1 site across 1 country: United States