Glucose Counterregulation in Long Standing Type 1 Diabetes

NCT ID: NCT01474889

Last Updated: 2023-08-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2021-03-05

Brief Summary

Enrollment for this study is complete.

This study is designed to determine if use of a real-time continuous glucose monitor (RT-CGM) can reverse defective Glucose counter regulation and hypoglycemia unawareness in long standing type 1 diabetes.

Detailed Description

The present protocol is designed to determine whether strict hypoglycemia avoidance by real-time continuous glucose monitoring (RT-CGM), can restore endogenous glucose production in response to hypoglycemia in patients with long standing disease. Twelve subjects with long standing type 1 diabetes complicated by hypoglycemia unawareness underwent assessment of the endogenous glucose production response to insulin-induced hypoglycemia using paired hyperinsulinemic euglycemic and hypoglycemic clamps with stable glucose isotope infusions before and at 6 and 18 months following initiation of RT-CGM. The primary analysis will be change in the endogenous glucose production response from before to 6 months following initiation of RT-CGM, and a secondary analysis will consider the persistence of any change at 18 months. The clinical significance of any determined changes in the endogenous glucose production response to insulin-induced hypoglycemia will be determined by comparison to responses obtained using paired hyperinsulinemic euglycemic and hypoglycemic clamps on one occasion in a matched control group of 12 subjects with long-standing type 1 diabetes but no hypoglycemia unawareness (GROUP 2) and in a matched control group of 12 nondiabetic subjects (GROUP 3).

Arms are not assigned to these two control groups in ct.gov as they were only used as a baseline for clinical significance. Neither group wore a CGM nor are they analyzed at 6-month and 18-month time-points. This said, for control group clarification, inclusion and exclusion criteria for each group is included in ct.gov

Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most patients with insulin-dependent diabetes. Type 1 diabetic patients with absolute insulin deficiency (C-peptide negative) are at greatest risk for experiencing severe hypoglycemic events because the near total destruction of insulin producing islet β-cells produces an associated defect in glucagon secretion from neighboring α-cells. Such patients then depend on the sympathoadrenal system as a final defense against hypoglycemia, but unfortunately, recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of hypoglycemia unawareness that is associated with a twenty-fold increased risk of life-threatening hypoglycemia. Without intact islet or sympathoadrenal (especially epinephrine) responses to hypoglycemia, these patients cannot increase endogenous (primarily hepatic) glucose production to prevent or correct low blood glucose.

Conditions

Hypoglycemia Unawareness; Type 1 Diabetes; Healthy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Hypoglycemia Unaware T1 Diabetes RT-CGM

This arm is the intervention group. It consists of participants with type 1 diabetes complicated by hypoglycemia unawareness. Patients wore an RT-CGM for 18 months. We studied glucose production and symptom generation during insulin-induced hypoglycemia (metabolic testing) by subjecting this intervention group to a pair of metabolic clamps (hypoglycemic and euglycemic) at baseline, at 6 months and at 18 months to determine if hypoglycemia avoidance can reverse unawareness.

Please note: Arms are not assigned to the two control groups (non-diabetics and T1Ds with intact awareness) in ct.gov as they are only used as a baseline for clinical significance. Neither group wore a CGM nor are they analyzed at 6-month and 18-month time-points.

Group Type: EXPERIMENTAL

RT-CGM

Intervention Type: DEVICE

Each device is approximately the size of a pager and transmits with a subcutaneously placed sensor consisting of a 21 - 26 gauge needle 5 - 12 mm in length. Sensors are placed using sterile precautions and changed every 3 - 7 days depending on the manufacturers' instructions. All devices are approved as adjunctive tools to blood glucose monitoring that will be continued at least 4 times daily, before each meal and at bedtime.

Interventions

RT-CGM

Each device is approximately the size of a pager and transmits with a subcutaneously placed sensor consisting of a 21 - 26 gauge needle 5 - 12 mm in length. Sensors are placed using sterile precautions and changed every 3 - 7 days depending on the manufacturers' instructions. All devices are approved as adjunctive tools to blood glucose monitoring that will be continued at least 4 times daily, before each meal and at bedtime.

Intervention Type: DEVICE

Other Intervention Names

DexCom SEVEN PLUS, Guardian R-T, or FreeStyle Navigator.

Eligibility Criteria

Inclusion Criteria

1. Male and female subjects aged 25 to 70 years

2. Able to provide written informed consent and to comply with the protocol procedures

3. Clinical history compatible with type 1 diabetes with disease onset < 40 years of age OR onset ≥ 40 years and documented islet autoimmunity

4. Insulin-dependent for > 10 years

5. Absent C-peptide (< 0.3 ng/mL).

6. Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.)

7. Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least one of the following:

• HYPO score greater than or equal to the 90th percentile (1047); OR marked glycemic lability defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile (433 mmol/l2/h·wk-1); OR
• A composite of a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than or equal to the 75th percentile (329).

8. At least one episode of severe hypoglycemia in the past 12 months defined as an event with symptoms or signs compatible with hypoglycemia in which the subject was unable to treat him/herself and which was associated with either a blood glucose level < 54 mg/dl [3.0 mmol/L] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration; OR documented > 5% time spent in the hypoglycemic range (glucose < 60 mg/dl) by 72-hour blinded CGM.

1. Male and female subjects aged 25 to 70 years.

2. Able to provide written informed consent and to comply with the procedures of the study protocol.

3. Clinical history compatible with type 1 diabetes with disease onset < 40 years of age

4. Insulin-dependent for > 10 years

5. Absent C-peptide (< 0.3 ng/mL).

6. Involvement in intensive diabetes management defined as the use of basal-bolus insulin analog delivery by multi-dose injection (MDI) or continuous subcutaneous insulin infusion (CSII) together with self-monitoring of blood glucose values four or more times daily, without continuous glucose monitoring (CGM), under the direction of an endocrinologist, diabetologist, or diabetes nurse practitioner with at least 3 clinical evaluations during the previous 12 months.

7. Intact hypoglycemia awareness indicated by a Clarke score of 3 or less.

8. No episodes of severe hypoglycemia in the past 3 years.

1. Male and female subjects aged 25 to 70 years.

2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.

3. No history of diabetes.

Exclusion Criteria

1. Body mass index (BMI) greater than 38 kg/m2.

2. Insulin requirement of more than 1.0 IU/kg/day.

3. HbA1c greater than 10%.

4. Untreated proliferative diabetic retinopathy.

5. SBP greater than 160 mmHg or DBP greater than 100 mmHg.

6. Glomerular filtration rate (GFR) less than 55 ml/min/1.73 m-squared

7. Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study.

8. Baseline hemoglobin less than 11 g/dl in women and less than12 g/dl in men.

9. Severe co-existing cardiac disease

10. Persistent elevation of liver function tests greater than 1.5 upper normal limits

11. Hyperlipidemia despite medical therapy

12. Receiving treatment for a medical condition requiring chronic use of systemic steroids

13. Presence of a seizure disorder not attributable to hypoglycemia.

14. Untreated hypothyroidism, Addisons disease, or Celiac disease.

15. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.

16. Use of RT-CGM (continuous glucose monitor) within last 4 weeks.

• Non-diabetic patients do not need to meet any of the glucose criteria.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Michael R. Rickels, MD, MS

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael R Rickels, M.D., M.S.

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Locations

Clinical and Translational Research Center, Hospital of University of Pennsylvania

Philadelphia, Pennsylvania, United States

Rodebaugh Diabetes Center, University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism

Philadelphia, Pennsylvania, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Rickels MR, Schutta MH, Mueller R, Kapoor S, Markmann JF, Naji A, Teff KL. Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab. 2007 Mar;92(3):873-9. doi: 10.1210/jc.2006-2426. Epub 2006 Dec 27.

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Rickels MR, Peleckis AJ, Dalton-Bakes C, Naji JR, Ran NA, Nguyen HL, O'Brien S, Chen S, Lee I, Schutta MH. Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes. J Clin Endocrinol Metab. 2018 Jan 1;103(1):105-114. doi: 10.1210/jc.2017-01516.

Reference Type: DERIVED

PMID: 29190340 (View on PubMed)

Other Identifiers

R01DK091331-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

814114

Identifier Type: -

Identifier Source: org_study_id