The goal of this study is to identify physiologic and molecular mechanisms that underlie hypoglycemia in the absence of diabetes (or medications that can cause hypoglycemia) and to investigate potential genetic and microbiome differences which contribute to hypoglycemia. We will test the hypothesis that hypoglycemia in the absence of diabetes is linked to genetic variation or the microbiome, and identify whether additional medical history or diagnoses are enriched in the population of patients with hypoglycemia.

Although there are several conditions which have been identified that cause, or contribute to hypoglycemia, diagnosis can be challenging, as the physiologic, and molecular mechanisms are incompletely understood. Additionally, treatment options are relatively limited, and often incompletely effective and/or not well tolerated. Investigating the causative factors and mechanisms of hypoglycemia is important therefore in improving our understanding in order to develop new and more effective approaches to treatment.

The current study aims to:

1. more fully characterize clinical history and demographics in patients with diverse forms of hypoglycemia by creating and analyzing a patient database;
2. for a subset of patients, characterize metabolic and hormonal responses to a standard meal;
3. analyze DNA variants in individuals with hypoglycemia;
4. analyze differences in the intestinal microbiome in individuals with hypoglycemia.

Inclusion Criteria:

1. For hypoglycemia group without a history of bariatric surgery: Males or females diagnosed with hypoglycemia with prior episodes of neuroglycopenia.
2. For hypoglycemia group with history of upper gastrointestinal surgery: Males or females diagnosed with ongoing hypoglycemia with prior episodes of neuroglycopenia.
3. For non-surgical controls only: Males or females with no history of upper gastrointestinal surgery and no history of hypoglycemia or diabetes.
4. Age 18-70 years of age, inclusive, at screening.
5. Willingness to provide informed consent and attend one study visit, with option to attend a second visit with mixed meal test, and follow all study procedures

Exclusion Criteria:

1. Active treatment with any diabetes medications except for acarbose;
2. Known insulinoma, gastrinoma, or other neuroendocrine tumor;

Additional exclusion criteria for those participating in optional Visit 2 (meal testing):

1. Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
2. Hepatic disease, including serum alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0;
3. Congestive heart failure, New York Hear Association (NYHA) class II, III or IV;
4. History of myocardial infarction, unstable angina or revascularization within the past 6 months or 2 or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use;
5. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia;
6. Concurrent administration of β-blocker therapy;
7. History of a cerebrovascular accident;
8. Seizure disorder (other than with suspect or documented hypoglycemia);
9. Active malignancy, except basal cell or squamous cell skin cancers;
10. Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
11. Major surgical operation within 30 days prior to screening;
12. Hematocrit < 33% (women) or <36% (men);
13. Bleeding disorder, treatment with warfarin, or platelet count <50,000;
14. Blood donation (1 pint of whole blood) within the past 2 months;
15. Active alcohol abuse or substance abuse;
16. Current administration of oral or parenteral corticosteroids;
17. Pregnancy and/ or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an intrauterine device (IUD), the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence.
18. Use of an investigational drug within 30 days prior to screening.

There will be no involvement of special vulnerable populations such as fetuses, neonates, pregnant women, children, prisoners, institutionalized or incarcerated individuals, or others who may be considered vulnerable populations.

3 groups: (1) patients with hypoglycemia, but without a history of bariatric or other gastrointestinal surgery, recruited from the Joslin Hypoglycemia Clinic, (2) patients with hypoglycemia and history of upper gastrointestinal surgery, recruited from the Joslin Hypoglycemia Clinic,(3) controls without hypoglycemia or surgery, recruited by local advertisement or from family members of patients with hypoglycemia. We plan to enroll patients with hypoglycemia continuously over the next 5 years.

Deidentified participant data may be shared with other researchers with permission of local institutional review boards.

6 months after publication of study results.

Data will be shared with academic investigators with approval of local institutional review boards.