The Effects of Hypoglycaemia in People With Type 2 Diabetes

NCT ID: NCT02205996

Last Updated: 2014-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-30
• Study Completion Date: 2013-05-31

Brief Summary

Strict glycaemic control has been associated with increased hypoglycaemia and mortality rate, the cause of which was unclear, in subjects with type 2 diabetes. In this study, we hypothesised that acute hypoglycaemia will result in platelet activation in people with type 2 diabetes to a higher degree than controls.

Detailed Description

Type 2 diabetes is associated with increased risk of cardiovascular disease. Although the United Kingdom Prospective Diabetes Study (UKPDS) follow-up data suggested reduced macrovascular complications with tight glycaemic control, recent studies in people with type 2 diabetes failed to replicate these findings. Furthermore, all-cause mortality was found to be increased with strict glycaemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The cause of the increased deaths remains unclear.

Strict glycaemic control is associated with increased risk of hypoglycaemia. Although, hypoglycaemia has traditionally been considered a complication of the treatment for type 1 diabetes, it has recently been recognised as a problem in people with type 2 diabetes particularly those on insulin therapy. In the ACCORD study, the risk of death was significantly increased in those with one or more episode of severe hypoglycaemia in both the strict and standard study treatment arms. As plasma glucose falls to below 4.0 mmol/L, a series of defence mechanisms occur, at an individualised glycaemic thresholds, to reverse hypoglycaemia including a rise in catecholamine levels. This may lead to hypokalaemia, prolonged QT interval, and cardiac arrhythmias. It may also lead to impaired cardiovascular autonomic function for up to 16 hours afterwards; increased inflammatory markers; platelet activation and promote vascular damage. As the majority of studies assessing the effects of hypoglycaemia on cardiovascular risk markers are conducted in people with type 1 diabetes and healthy controls, their findings may not necessarily be applicable to people with type 2 diabetes. In particular, the effects of hypoglycaemia on platelet function and thrombotic risk in people with type 2 diabetes require further clarification. In this study, we hypothesised that acute hypoglycaemia will result in platelet activation in people with type 2 diabetes to a higher degree than controls.

Conditions

Type 2 Diabetes Mellitus

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Controls

Weight-matched healthy controls. Euglycaemic Hypoglycaemic insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.

Group Type: ACTIVE_COMPARATOR

Insulin (Humulin S)

Intervention Type: DRUG

Using insulin and glucose infusions (hyperinsulinaemic clamps), blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.

Euglycaemic Hypoglycaemic Insulin clamp

Intervention Type: DEVICE

Type 2 diabetes

People with a known diagnosis of type 2 diabetes. Euglycaemic Hypoglycaemic Insulin clamp. Using hyperinsulinaemic clamps, blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.

Group Type: ACTIVE_COMPARATOR

Insulin (Humulin S)

Intervention Type: DRUG

Using insulin and glucose infusions (hyperinsulinaemic clamps), blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.

Euglycaemic Hypoglycaemic Insulin clamp

Intervention Type: DEVICE

Interventions

Insulin (Humulin S)

Using insulin and glucose infusions (hyperinsulinaemic clamps), blood glucose levels were stabilised over 1 hour to reach 5 mmol/L and maintained at that level for 1 hour, then gradually reduced over 1 hour to 2.8 mmol/L and maintained at that level for 1 hour. Blood samples were collected at times 0 (baseline), 2 hours (euglycaemia), 4 hours (hypoglycaemia) and at 24 hours after the clamp studies.

Intervention Type: DRUG

Euglycaemic Hypoglycaemic Insulin clamp

Intervention Type: DEVICE

Other Intervention Names

Glucose (20% Dextrose).

Eligibility Criteria

Inclusion Criteria

1. Healthy volunteers:

• Males or females
• On no medications except for the contraceptive pill and without medical illnesses in the last three months.
• Non-smokers
• 40 - 60 years of age.

2. T2DM subjects:

• Males or females
• Diagnosis of T2DM
• 40 - 60 years of age
• HbA1C: 6.5 - 9.5%
• Duration of diabetes 1 - 10 years
• Diabetes treated with diet, or tablets only.

Exclusion Criteria

1. Healthy volunteers:

• Pregnancy
• Lack of contraception in women of child bearing age
• Chronic medical conditions
• Current smokers
• Evidence of ischaemia on ECG
• Drop attacks
• Alcohol or drug abuse
• Psychiatric illness
• Previous history of seizure
• Alcohol or drug abuse

2. Type 2 diabetes subjects:

• Pregnancy
• Current smokers
• Recurrent episodes of hypoglycaemia
• Treatment with anti-platelet or anti-coagulation therapy
• History of ischaemic heart disease, stroke or peripheral vascular disease
• Epilepsy
• Drop attacks
• Evidence of ischaemia on ECG
• Insulin treated T2DM
• History of microvascular disease (retinopathy, nephropathy or neuropathy).
• Alcohol or drug abuse
• Psychiatric illness

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hull University Teaching Hospitals NHS Trust

OTHER_GOV

Sponsor Role: collaborator

University of Hull

OTHER

Sponsor Role: lead

Responsible Party

Thozhukat Sathyapalan

Dr

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stephen L Atkin, PhD

Role: PRINCIPAL_INVESTIGATOR

Hull York Medical School

Locations

Hull Royal Infirmary

Hull, , United Kingdom

Countries

United Kingdom

References

Moin ASM, Sathyapalan T, Atkin SL, Butler AE. The severity and duration of Hypoglycemia affect platelet-derived protein responses in Caucasians. Cardiovasc Diabetol. 2022 Oct 6;21(1):202. doi: 10.1186/s12933-022-01639-w.

Reference Type: DERIVED

PMID: 36203210 (View on PubMed)

Moin ASM, Nandakumar M, Kahal H, Sathyapalan T, Atkin SL, Butler AE. Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia. Cells. 2021 Nov 10;10(11):3109. doi: 10.3390/cells10113109.

Reference Type: DERIVED

PMID: 34831332 (View on PubMed)

Moin ASM, Kahal H, Al-Qaissi A, Kumar N, Sathyapalan T, Atkin SL, Butler AE. Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia. BMJ Open Diabetes Res Care. 2021 Apr;9(1):e002211. doi: 10.1136/bmjdrc-2021-002211.

Reference Type: DERIVED

PMID: 33931404 (View on PubMed)

Other Identifiers

11/YH/0161

Identifier Type: -

Identifier Source: org_study_id