Fasting hyperglycemia contributes disproportionately to nonenzymatic glycosylation and the microvascular complications of type 2 diabetes. However, little is known about the regulation of glucose concentrations in the fasting state relative to what is known about the postprandial state. The proposed experiment is part of a series of experiments designed to establish how glucagon and insulin interact with their receptors to control fasting glucose in health and in prediabetes.

Decreased insulin action increases glucagon concentrations. In rodents, insulin signaling restrains glucagon secretion. It is unclear if this is the case in all (subtypes of) prediabetes. Impaired hepatic insulin action exacerbates glucagon's effects on endogenous glucose production. Also, insulin resistance in the β-cell impairs negative feedback inhibition of insulin secretion. This leads to hyperinsulinemia in rodents and humans. How these variables interact is unknown. This experiment will determine how insulin variably regulates fasting glucagon (and insulin) secretion directly, or indirectly, in prediabetes.

The inability of the proinsulin to insulin ratio to reliably predict β-cell integrity, endoplasmic reticulum stress and β-cell function has led to the identification of novel markers of β-cell health. In addition, the relationship of glucagon and insulin pulses will be quantified. Preliminary data shows that there is heterogeneity in these relationships even in normal fasting glucose. Th experiment will also determine how islet hormone / glucose crosstalk and pulse characteristics contribute to prediabetes.

Inclusion Criteria:

• people with normal or impaired fasting glucose and normal or impaired glucose tolerance

Exclusion Criteria:

1. HbA1c > 6.5%
2. BMI ≥ 35 Kg/M2
3. Use of any glucose-lowering agents including metformin or sulfonylureas.
4. For female subjects: positive pregnancy test at the time of enrollment or study
5. History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
6. Active systemic illness or malignancy.
7. Symptomatic macrovascular or microvascular disease.
8. Hematocrit < 35%

Data that will be preserved and shared include results of screening labs, immunoassay data and glucose turnover data. In addition, we will share the study protocol, statistical analysis plan, a data dictionary and anonymization guidance (methodology to anonymize data).In addition to the patient-level data, the metadata, data dictionary, statistical analysis plan, and final protocol will be shared. The sharing of the data dictionary, statistical analysis plan and final protocol with amendments will enable researchers to understand how the data was collected and to correctly interpret the data for future secondary analysis. The final patient level dataset will include demographics as well as screening data and primary and secondary outcomes.We plan to share datasets resulting from the proposed studies in Vivli, a non-profit institution that supports the Vivli repository.

The data shared will be archived and available on the platform for request by researchers for a minimum of 10 years after contribution. Data will be made accessible no later than the time of our associated publication or the end of the grant period (whichever comes first). On an ongoing basis, Vivli evaluates its data holdings regarding maintaining access and reserves the right to discontinue the distribution of a data collections when deemed appropriate. When materials are deaccessioned, the data are no longer publicly accessible at Vivli, they may still be preserved in Vivli's storage vault. Because digital files are assigned a persistent digital object identifier (DOI), the study description is still available to view, but is not searchable through Vivli.

The data being shared is human data from clinical trials and therefore a higher level of protection is required. Access to this data will be controlled by a managed access process whereby access is provided only after approval. Data will be controlled access with the General Research Use Data Use Limitation, as allowed by the informed consent and the institutional certification.