Background and Significance: The peptide hormone ghrelin drives hunger and feeding behavior, making it a focus of obesity research. Released mainly by the stomach and proximal small intestine, ghrelin peaks prior to meals, potentially priming the gut for anticipated nutrients. After eating, ghrelin abruptly declines, with levels varying 2- to 3-fold between the fasted and fed states. Interestingly, in obesity and type 2 diabetes (T2D), this pattern is disrupted. Individuals with these disorders have chronically suppressed ghrelin levels and little variation before and after meals.

Although ghrelin's preprandial rise and postprandial fall is a well-established phenomenon, its role in regulating glucose metabolism is unclear. In mice, increasing preprandial ghrelin levels improves glucose tolerance through enhanced glucagon-like peptide-1 (GLP-1) secretion. Ghrelin also stimulates GLP-1 secretion from mouse and human intestinal L-cells in vitro. These findings suggest enhanced postprandial GLP-1 as a novel role for the preprandial ghrelin surge. A ghrelin-incretin enteroendocrine axis could also explain the poor postprandial GLP-1 secretion and glucose tolerance in subjects with T2D, given their preprandial hypoghrelinemia.

The investigators' preliminary data demonstrate that in humans, increasing circulating ghrelin to a supraphysiologic range worsened glucose tolerance, despite increased GLP-1 secretion. The discrepancy between these findings and the ones from rodents could be due to difference in study design and/or species. For example, the investigators' study used a continuous ghrelin infusion, which resulted in elevated levels of ghrelin pre- and postprandially. Elevated postprandial ghrelin likely mitigated the positive effects of increased GLP-1 secretion by raising levels of glucagon and other counter-regulatory hormones.

This study seeks to delineate the interactions between ghrelin and GLP-1 in the regulation of glucose tolerance, beta-cell function, and insulin sensitivity. The investigators hypothesize that increased preprandial ghrelin will enhance GLP-1 secretion and consequently improve glucose tolerance in healthy subjects and those with T2D. Confirmation of these hypotheses would advance the investigators understanding of the control of glucose homeostasis and have important clinical and therapeutic implications. Modulating ghrelin levels may provide a novel therapeutic strategy to improve glucose tolerance in individuals with T2D, which affects an estimated 350 million people worldwide.

Inclusion Criteria:

T2DM study subjects must meet the following inclusion criteria:

• established T2DM with good to moderate glycemic control (HbA1c ≤ 8.5%)
• Diabetes treated with oral medications or lifestyle management
• BMI 25.0 - 45.0 kg/m2

Healthy control subjects must meet the following inclusion criteria:

• Fasting glucose <100 mg/dL, as measured at screening visit
• HbA1c < 5.7%, as measured at screening visit
• BMI 18.0 - 29.9 kg/m2
• No diagnosis of diabetes mellitus (including gestational diabetes)
• Age between 18 - 40 years

Exclusion Criteria:

All subjects will be excluded for the following reasons:

• Active infections
• History of malignant or inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease
• History of myocardial infarction or congestive heart failure
• History or active liver or renal disease (AST or ALT >2x upper limits of normal, calculated glomerular filtration rate [eGFR] <60 at screening)
• Anemia defined as hematocrit <34% at screening visit
• Uncontrolled hypertension
• History of pituitary or adrenal disorders or neuroendocrine tumor
• History of anorexia nervosa or previous gastrointestinal surgery
• Malabsorptive GI disease, such as celiac disease
• Pregnancy or lactation
• Use of medications that alter glucose metabolism or GI function (glucocorticoids, psychotropics, niacin, narcotic, metoclopramide)
• Use of insulin or GLP-1 based therapy (i.e. DPP-4 inhibitors, GLP-1 receptor agonists)