KATP Channel Loss for Type 2 Diabetes

(BC Trial)

Recruiting at 1 trial location

Overseen By Kyle Timmons

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Washington University School of Medicine

Must not be taking: Steroids, Anticoagulants, others

Disqualifiers: Organ dysfunction, Tobacco use, Alcohol, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 1 day

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how the KATP channel in pancreas cells affects insulin secretion in individuals with and without type 2 diabetes. Researchers will administer glipizide, a medication that blocks these channels, to observe its impact on blood sugar control. The trial seeks participants with various body types and glucose levels, including those with obesity and type 2 diabetes, to help explore better diabetes management methods. As an unphased trial, this study offers participants the chance to contribute to foundational research that could lead to improved diabetes management strategies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those who have changed their diabetes medication in the past 3 months or use medications that could affect the study's outcomes. It's best to discuss your specific medications with the research team.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research has shown that glipizide, the treatment under study, is generally well-tolerated in people with type 2 diabetes. One study found that glipizide lowered fasting blood sugar levels and improved HbA1c, a measure of long-term blood sugar control. However, concerns exist about its heart safety. Specifically, another study found a slightly higher risk of major heart problems, such as heart attacks, with glipizide compared to some other diabetes medications.

Overall, the FDA has approved glipizide for managing type 2 diabetes, indicating its safety for this condition. Nonetheless, discussing potential risks with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using Glipizide for Type 2 Diabetes because it targets the KATP channels in the pancreas, which play a key role in insulin secretion. While standard treatments like Metformin primarily focus on improving insulin sensitivity or reducing glucose production, Glipizide stimulates the pancreas directly to produce more insulin. This mechanism can be particularly beneficial for those whose bodies struggle to produce enough insulin naturally. Additionally, by focusing on KATP channels, Glipizide offers a unique approach that complements existing treatments, potentially leading to more effective blood sugar management.

What evidence suggests that this trial's treatment could be effective for type 2 diabetes?

Research has shown that glipizide, the investigational treatment in this trial, effectively lowers blood sugar levels. Studies have found that it can significantly reduce fasting blood sugar by 57 to 74 mg/dl and lower HbA1c by 1.50 to 1.82%. Glipizide helps the body release more insulin, which is crucial for controlling blood sugar. Combining glipizide with other medications like metformin can further enhance blood sugar control. Overall, glipizide has proven effective in managing blood sugar levels in people with type 2 diabetes. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with type 2 diabetes, who may also have high blood pressure and obesity. Participants should not be on any medication that affects KATP channels or insulin secretion. Pregnant women and individuals with other significant health issues are excluded.

Inclusion Criteria

I am obese with a BMI between 30 and 50, normal blood sugar levels, and no diabetes.

Lean-normoglycemic group: BMI ≥18.5 and <25.0 kg/m², fasting plasma glucose concentration <100 mg/dl, 2-hr oral glucose tolerance test plasma glucose concentration ≤140 mg/dl, and hemoglobin A1C (HbA1C) ≤5.6%

I am obese with a BMI between 30 and 50, have type 2 diabetes, and am on medication for it.

Exclusion Criteria

I do not have major organ problems except for obesity and type 2 diabetes.

Unstable weight (>2% change during the last 2 months before entering the study)

Regular use of tobacco products

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of the KATP antagonist glipizide (5mg) to assess insulin secretion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for insulin secretion and KATP channel activity after glipizide ingestion

90 minutes

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Glipizide

Trial Overview

The study tests the effects of a single dose of glipizide, a drug that inhibits KATP channels in the pancreas, which could affect insulin release and blood sugar control in people with type 2 diabetes compared to those without it.

How Is the Trial Designed?

Group I: Obesity with type 2 diabetes Experimental Treatment 1 Intervention

Body mass index ≥30 and \<50 kg/m²; HbA1C 6.5-9.5%, fasting plasma glucose ≥126 mg/dl, 2-hr oral glucose tolerance test plasma glucose concentration ≥200 mg/dl and/or medical history of type 2 diabetes and currently using anti-diabetic medications.

Group II: Obesity with normal glucose tolerance Experimental Treatment 1 Intervention

Body mass index ≥30 and \<50 kg/m², fasting plasma glucose concentration \<95 mg/dl, 2-hr oral glucose tolerance test plasma glucose concentration ≤140 mg/dl, and hemoglobin A1C (HbA1C) ≤5.6%.

Group III: Obesity with impaired fasting glucose Experimental Treatment 1 Intervention

Body mass index ≥30 and \<50 kg/m², fasting plasma glucose concentration 100-125 mg/dl, and 2-hr oral glucose tolerance test plasma glucose concentration \<200 mg/dl.

Group IV: Lean with normal glucose tolerance Experimental Treatment 1 Intervention

Body mass index ≥18.5 and \<25.0 kg/m², fasting plasma glucose concentration \<95 mg/dl, 2-hr oral glucose tolerance test plasma glucose concentration ≤140-mg/dl, and hemoglobin A1C (HbA1C) ≤5.6%.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

Sulfonylureas play a crucial role in regulating glucose-induced electrical activity in pancreatic beta-cells by interacting with ATP-sensitive K channels (KATP), which are essential for insulin secretion.

Recent advancements in understanding the sulfonylurea receptor and KATP channel may provide insights into their complex regulation and improve our knowledge of beta-cell function in diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The beta-cell response to oral hypoglycemic agents. Cook, DL.[2019]

The study highlights the importance of ATP-sensitive K+ (KATP) channels in insulin secretion, showing that their absence leads to a shift in G protein signaling in β cells, which affects how incretins like GLP-1 and GIP function in type 2 diabetes (T2D).

GLP-1 can effectively enhance insulin secretion in KATP channel-deficient models, while GIP cannot, suggesting that targeting GLP-1 signaling may be a more effective strategy for improving insulin response in patients with T2D.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression? Nichols, CG., York, NW., Remedi, MS.[2021]

Mice lacking KATP channels (Kir6.2(-/-)) show a significant inability to secrete insulin in response to glucose or the drug tolbutamide, indicating that KATP channels are crucial for insulin secretion in pancreatic beta cells.

Despite their impaired insulin secretion, Kir6.2(-/-) mice exhibit only mild glucose tolerance impairment and enhanced insulin sensitivity, suggesting that other mechanisms may help prevent hyperglycemia in the absence of KATP channels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Miki, T., Nagashima, K., Tashiro, F., et al.[2023]

Suppression of KATP channel activity can partially protect beta cells from damage caused by glucolipotoxicity (GLTx), but it does not prevent the reduction in insulin secretion or content, indicating that GLTx directly interferes with the beta cell's secretory capacity.

GLTx leads to energy depletion in beta cells, reducing mitochondrial membrane potential and ATP levels, which is a key factor in the loss of beta cell function in type-2 diabetes, independent of reactive oxygen species (ROS) production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Energy depletion and not ROS formation is a crucial step of glucolipotoxicity (GLTx) in pancreatic beta cells. Barroso Oquendo, M., Layer, N., Wagner, R., et al.[2019]

In a study involving 43 Zucker obese diabetic fatty rats, low-dose diazoxide (DZX) was found to promote the occurrence of ventricular tachyarrhythmias (VTs) during ischemic conditions, indicating a potential risk for diabetic patients.

DZX caused rapid and uneven shortening of action potential duration in T2DM hearts, which led to arrhythmias, suggesting that it should be avoided in diabetic patients who are at risk for ischemic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus. Xie, C., Hu, J., Motloch, LJ., et al.[2022]

Prolonged exposure to diazoxide, a KATP channel opener, enhances insulin secretion from beta cells, suggesting it may have protective effects on beta cell function after 18 hours of treatment.

In contrast, prolonged exposure to KATP channel blockers like nateglinide and tolbutamide reduces insulin secretory responses to certain stimuli, indicating that chronic blockade can be harmful to insulin secretion mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations of insulin secretion following long-term manipulation of ATP-sensitive potassium channels by diazoxide and nateglinide. Ball, AJ., Flatt, PR., McClenaghan, NH.[2018]

Transgenic mice with beta cell K(ATP) channels that have reduced sensitivity to ATP developed severe hyperglycemia and hypoinsulinemia within just 2 days, leading to ketoacidosis and typically death within 5 days, highlighting the critical role of K(ATP) channel activity in insulin secretion.

The study demonstrates that normal functioning of K(ATP) channels is essential for maintaining normal blood sugar levels (euglycemia), and that decreased responsiveness of these channels can directly cause diabetes by impairing insulin release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Koster, JC., Marshall, BA., Ensor, N., et al.[2019]

In pancreatic beta cells of NIDDM rats, the KATP channels show reduced sensitivity to glucose, which is a key factor in impaired insulin secretion in diabetes.

The study suggests that the impairment in glucose-induced insulin secretion is linked to the glycerol phosphate shuttle, as KATP channel function remains normal when stimulated by certain agents like glyceraldehyde.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced dihydroxyacetone sensitivity and normal sensitivity to glyceraldehyde and oxidizing agent of ATP-sensitive K+ channels of pancreatic beta cells in NIDDM rats. Song, DK., Park, WK., Bae, JH., et al.[2015]

In normal mice, glucose-induced secretion of the gut hormone GIP primarily relies on the sodium glucose co-transporter 1 (SGLT1), while the KATP channels do not play a significant role.

In diabetic mice, both SGLT1 and KATP channels are involved in GIP secretion, indicating that the mechanism of GIP release changes depending on the glucose metabolism state.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state. Ogata, H., Seino, Y., Harada, N., et al.[2022]

Transgenic mice expressing a dominant-negative form of the KATP channel subunit Kir6.2 developed significant metabolic issues, including hypoglycemia with hyperinsulinemia in neonates and hyperglycemia with hypoinsulinemia in adults, indicating the critical role of KATP channels in glucose regulation.

The study revealed that impaired KATP channel function in pancreatic beta cells led to increased apoptosis and altered cellular conditions, suggesting that KATP channels are essential not only for insulin secretion but also for the survival of beta cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Miki, T., Tashiro, F., Iwanaga, T., et al.[2019]

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