Hyperinsulinemic hypoglycemia precipitated by weight loss.

Objective: To describe a case of hyperinsulinemic hypoglycemia precipitated by weight loss.

Methods: We present a detailed case report and results of a related literature search on hyperinsulinemic hypoglycemia precipitated by weight loss.

Results: The presence of an insulinoma was unveiled by voluntary weight loss and reduction of insulin resistance. Hypoglycemia occurred during the postprandial period and not at night. The diagnostic workup was accomplished without hospital admission.

Conclusion: Classically, insulinomas present with weight gain and fasting hypoglycemia but may present with postprandial hypoglycemia and weight loss. Voluntary weight loss, by lowering insulin resistance, accelerates the time to clinical presentation of an asymptomatic insulinoma.

Key Words: hyperinsulinemic hypoglycemia, insulinoma, outpatient diagnosis of insulinoma, postprandial hypoglycemia, voluntary weight loss

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Insulinomas typically present with fasting hypoglycemia, neuroglycopenic symptoms, and inappropriate insulin secretion. In response to these symptoms, patients often tend to increase their food intake and gain weight. We report the case of a patient in whom an insulinoma was diagnosed in the context of rapid weight loss and postprandial, rather than fasting, hypoglycemia.

Case Report

A 56-year-old white male presented for evaluation of hypoglycemia. In the preceding four months he had joined a local Weight Watchers program and had lost 70 pounds. Two weeks before presentation, he noticed episodes of confusion, disorientation, and diplopia occurring 3 to 4 hours after eating. There was no history of fasting or nocturnal symptoms. During one of his symptomatic periods, he left work, drove through three red lights and on arriving at home, drank a shot of whiskey in an attempt to alleviate his symptoms. His wife found him in a confused state and unable to operate the television remote control. Since her mother was diabetic and was often hypoglycemic, she gave him orange juice, and he promptly recovered. He subsequently noticed that similar symptoms could be reversed by consuming sugar-containing beverages or food.

The patient's past medical history was remarkable only for a mild depression which was being treated with paroxetine hydrochloride. The only significant family history was type 2 diabetes mellitus in his father. The patient did not smoke and drank alcohol only occasionally. Examination revealed a 6'3", 292 pound gentleman with a BMI of 36.7. The remainder of the examination was normal.

A 3-hour postprandial plasma glucose of 42 mg/dL was documented in his primary care physician's office, and on his first endocrinology visit, a fasting plasma glucose was 86 mg/dL. Glycosylated hemoglobin was 4.9%. An outpatient fast was initiated. Since he had no fasting or nocturnal symptoms and his wife agreed to drive him to the clinic, the fast was started at 6:00 PM the previous evening. After 16 hours (10:00 AM) the patient became symptomatic with a serum glucose level of 36 mg/dL and an insulin level of 6.5 mcU/mL. Therefore, the requirements for Whipple triad was satisfied since his symptoms and serum glucose quickly responded to oral glucose administration. Glucagon was not administered at the end of the fast. The inappropriately elevated insulin level > 6 U/mL in the setting of a serum glucose concentration lower then 45 mg/dL indicated hyperinsulinemic hypoglycemia and further workup was performed. Fasting C-peptide was 2.9 ng/mL and cortisol and growth hormone responses to hypoglycemic stimulation were adequate. A urine screen for sulfonylureas was negative and at the time of hypoglycemia, ketones were absent from both the serum and urine. Thyroid, liver, and renal function tests and a serum calcium level were normal.

A contrasted abdominal CT scan was within normal limits; however, an endoscopic ultrasound revealed a 12 X 10 mm hypoechoic mass in the neck of the pancreas just above the portal vein confluence. Endoscopic surgery was performed with successful enucleation of a benign insulinoma. Postoperatively, the patient developed intestinal obstruction from an internal herniation that was successfully managed. The patient subsequently did well with both relief of hypoglycemic symptoms and normalization of serum glucose. He was able to continue his Weight Watchers program, losing an additional 9 pounds within the next month.

Discussion

This case is unusual in that the patient's hypoglycemia was associated with weight loss. Usually hypoglycemia is associated with a weight gain due to increased caloric intake stimulated by hypoglycemia. We hypothesize that this patient's hypoglycemia occurred several years earlier than normal as a result of the patient's voluntary weight loss. By reducing his BMI from 45.5 to 36.7, we estimate that this 19% weight loss resulted in a 31% decrease in insulin resistance. (1) We also postulate that the patient's weight gain (30 pounds in the year before starting his diet) was due to hyperinsulinemia. We believe that this weight gain would have continued with increasing insulin resistance until the insulinoma grew to a size where enough insulin was produced to overcome the patient's insulin resistance, and at this time, hypoglycemia would have occurred. In other words, the weight reduction diet short-circuited the normal series of events (hyperinsulinemia, hyperphagia, weight gain, increasing insulin resistance, tumor growth, and then hypoglycemia) and led to removal of the insulinoma at an earlier stage of growth.

A second unusual feature of this case is that this patient had no nocturnal or early morning hypoglycemia or precipitation of hypoglycemia with exercise and presented with postprandial late-morning hypoglycemia. His symptoms would consistently occur 3 to 4 hours after ingestion of food. This was not true postprandial hypoglycemia, however, because when fasting, the patient's hypoglycemic symptoms occurred at exactly the same time of the day. Therefore, this was most likely a fasting hypoglycemia that was unaffected by a low-calorie breakfast. We postulate that he became hypoglycemic at this time due to lowering of insulin resistance. The "dawn phenomenon" describes the time of day when insulin resistance, due to nocturnal growth hormone spikes, is at its highest, and in diabetic patients, increased basal insulin is required during this 4 to 5 hour period which ends 2 to 3 hours after breakfast. (2) Since calorie restriction increases growth hormone levels, his low-calorie diet could have further impeded the development of hypoglycemia. (3) We also believe that nocturnal hypoglycemia may well have been present and not recognized by the patient since even nondiabetic children sleep through nocturnal hypoglycemia. (4) The existence of a dawn phenomenon in nondiabetic individuals is still a matter of controversy. If present, it has been attributed to a transient fall in insulin sensitivity and an increase in insulin clearance. (5,6)

A third unusual feature of this case is that we managed to completely work up the patient's hypoglycemia without admitting him to the hospital. Usually fasting is started as an outpatient and if hypoglycemia has not occurred by midafternoon on the first day of the fast, the patient is admitted to the hospital so that fasting and observation can continue. Therefore, under normal circumstances, the fast would only be 8 to 10 hours old at this point, and only a third of insulinoma-induced hypoglycemias would have occurred (7). In this case, since the patient had no nocturnal events and was driven to the outpatient facility, we felt comfortable starting the fast the evening before and were therefore able to diagnose hyperinsulinemic hypoglycemia after a sixteen hour fast in the outpatient setting. Furthermore, as the anatomic diagnosis of the insulinoma was made utilizing endoscopic ultrasound, the need for more invasive, inpatient testing, such as celiac angiography, was not required.

Conclusion

In conclusion, we have described an unusual case of hyperinsulinemic hypoglycemia due to an insulinoma, the effects of which were precipitated by voluntary weight loss and lowering of insulin resistance. Furthermore, the presentation was unusual in that the hypoglycemia presented in the postprandial state (even though it was reproduced during a supervised fast) and the diagnostic workup was accomplished in the outpatient setting.

References

1. Goodpaster BH, Kelley DE, Wing RR, et al. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 1999;48:839-847.

2. Campbell PJ, Bolig GB, Cryer PE, et al. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 1985;312:1473-1479.

3. Douyon L, Schteingart DE. Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. Endocrinol Metab Clin North Am 2002;31:173-89.

4. Jones TW, Porter P, Sherwin RS, et al. Decreased epinephrine responses to hypoglycemia during sleep. New England Journal of Medicine 1998;23:1657-1662.

5. Bolli GB, De Feo P, De Cosmo S, et al. Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 1984;33:1150-1153.

6. Simon C, Brandenberger G, Follenius M. Absence of the dawn phenomenon in normal subjects. J Clin Endocrinol Metab 1988;67:203-20.

7. Hirshberg B, Livi A, Bartlett DL, et al. Forty-eight hour fast: the diagnostic test for insulinoma. JCEM 2000;85:3222-3226.

Maria S. Prelipcean, MD, Patrick J. O'Neil, MB, and David S. H. Bell, MB

From the University of Alabama Medical School, Birmingham, AL; and Family Practice, Madison, AL.

Reprint requests to David S.H. Bell, MB, FACE, Faculty Office Tower, Room 702, 510 South 20th Street, Birmingham, AL 35294. Email: [e-mail]

Accepted January 14, 2005.

RELATED ARTICLE: Key Points

* Insulinoma revealed by voluntary weight loss.

* Hyperinsulinemia can present with postprandial hypoglycemia.

* Insulinoma can be diagnosed in an outpatient setting.