Etiology, Assessment and Treatment of Post-gastric Bypass Severe Hypoglycemia
Condition: Obesity; Hypoglycemia; Surgery
MeSH terms: Hypoglycemia
Study type: Interventional

Summary: 
      With increasing rates of obesity the number of anti-obesity operations performed is
      increasing; one of the most common is gastric bypass. Anti-obesity surgery ameliorates
      diabetes and several other serious comorbidities, but bariatric surgery is also associated
      with medical and nutritional complications.

      Post-gastric bypass hyperinsulinemic hypoglycemia is a relative rare but serious complication
      often seen months to years after gastric bypass surgery. The patients experience
      neuroglycopenic symptoms (eg. inability to concentrate, weakness, altered mental status, loss
      of consciousness).

      The purpose of this study is to determine whether glucagon-like peptide-1 (GLP-1)or other
      enteropancreatic factors (eg. gastric emptying rate) are responsible for the excessed insulin
      secretion seen in some patients after bariatric surgery.
    

Detailed description: 
      The increasing prevalence of obesity has led to parallel increase in bariatric surgery.
      Sustained weight reductions of up to 50 % of excess body weight are achieved in the majority
      of patients, and bariatric surgery is more effective in producing sustained weight loss.
      Another remarkable effect of bariatric surgery, especially Roux-en-Y gastric bypass (RYGB),
      is the profound and durable resolution of clinical manifestations of type 2 diabetes. Despite
      the favorable effects of bariatric surgery on obesity-associated morbidity and mortality,
      there has been mounting concerns about severe hypoglycemia associated with Roux-en-Y gastric
      bypass surgery.

      This is an increasingly recognized condition characterized by neuroglycopenia and
      inappropriately elevated insulin concentrations. The patients experience autonomic symptoms
      with tremor, palpitation, sweating and hunger, and symptoms of neuroglycopenia such as
      inability to concentrate, weakness, drowsiness and behavioral changes. One issue complicating
      the characterization of post-gastric bypass surgery is that patients who have undergone
      bariatric surgery typically experience numerous post-prandial symptoms including the "dumping
      syndrome", which may be part of a continuum of post-gastric bypass hypoglycemia. We know that
      affected individuals have exaggerated insulin and glucagon-like peptide-1 response to meal
      consumption compared with asymptomatic individuals with prior gastric bypass surgery.

      Ten patients with recurrent hypoglycemia events, including the presence of Whipple's triad,
      following gastric bypass surgery will participate in this study. Ten asymptomatic subjects
      with previous gastric bypass surgery and 10 control subjects with normal glucose tolerance
      and no prior gastrointestinal surgery will be recruited. Ten subjects with prior
      sleeve-gastrectomi will also participate in order to see if this operation is more beneficial
      in avoiding post-gastric bypass hypoglycemia.

      Pre- and postprandial hormone levels and insulin secretion rates in response to 50 mg oral
      glucose tolerance test (OGTT), isoglycemic intravenous glucose infusion (IIGI) and 300 kcal
      liquid mixed meal will be measured in 3 different days separated by an interval of at least 1
      week. These tests will be performed to see how the response to intravenous versus per oral
      glucose stimulation differ in the four different groups in regard to biomedical markers and
      symptoms of hypoglycemia.

      All participants will wear Continuous Glucose Monitoring (CGM) for at least 5 days. During
      this period of time the subjects will be asked to come to the laboratory on two separate days
      to receive a high-carbohydrate meal and a low-carbohydrate meal respectively. The ingestion
      of the will be followed by three hours blood glucose measurements along with the CGM. The
      purpose of these test are to see the different response in glucose depending on the
      composition of the meal ingested, and to see whether CGM is reliably especially for measuring
      low levels of glucose.

      The subjects with recurrent hypoglycemia events following gastric bypass surgery will receive
      the liquid mixed meal three times separated by at least one week; first as described earlier
      without receiving any drug and afterwards receiving either Exendin 9-39 (a specific GLP-1
      receptor antagonist) or a Octreotid (Somatostatin analog). The purpose of these tests are to
      test the hypothesis that gastric bypass surgery associated hyperinsulinemic hypoglycemia is
      mediated by increased GLP-1 actions. Furthermore we use the somatostatin analog to test
      whether an inhibition of other gastroenteropancreatic hormones and a delay in gastric
      emptying of solids will change the glucose-insulin metabolism. To evaluate the impact of
      these pharmacologically interventions on gastric emptying rate we use acetaminophen
      absorption test.

      Aim:

        1. Is GLP-1 or other gastroenteropancreatic hormones pathophysiologically involved in the
           development of post-gastric bypass hyperinsulinemic hypoglycemia?

        2. To investigate whether CGM can be used to diagnose hypoglycemia after gastric bypass
           surgery?

        3. Which nutritional and pharmacological options do we have in managing the treatment of
           this condition?
    

Intervention name(s): Oral Glucose tolerance test (OGGT); Liquid mixed meal; Octreotide
Intervention type(s): Dietary Supplement; Dietary Supplement; Drug
Intervention description(s): At baseline subjects will consume 50 g glucose dissolved in water in 10 minutes; At baseline subject will consume the liquid mixed meal in 10 minutes; At baseline subjects will receive Octreotid 100 µg subcutaneous
Other intervention name(s): Liquid mixed meal containing carbohydrate, fat and proteins; Somatostatin analogue
Intervention MeSH terms: Octreotide; Somatostatin
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Glucagon like peptide 1; Insulin secretion; Hypoglycemia