Natural History of a Proinsulin-Secreting Insulinoma: From Symptomatic Hypoglycemia to Clinical Diabetes

Elif Arioglu, Nicole A. Gottlieb, Christian A. Koch, John L. Doppman, Neil J. Grey and Phillip Gorden

Diabetes Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases (E.A., N.A.G., P.G.), National Institute of Child Health and Human Development (C.A.K.), Diagnostic Radiology Department (J.L.D.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and Medical Director of Diabetes Life Care, School of Medicine, University of Connecticut (N.J.G.), Hartford, Connecticut 06105

Address correspondence and requests for reprints to: Phillip Gorden, M.D., National Institutes of Health, NIDDK Director, Building 10, Room 8S235, Bethesda, Maryland 20892. E-mail: phillip_gorden{at}nih.gov


    Introduction
 Top
 Introduction
 Case Report
 Discussion
 References
 
Insulinoma, an islet cell tumor of the pancreas, is clinically characterized by symptomatic hypoglycemia, an inappropriately increased plasma insulin level, and an increased proinsulin concentration. Current imaging and surgical techniques usually permit localization and resection of these mostly benign islet cell tumors with resolution of hypoglycemic symptoms.

The association of diabetes mellitus and insulinoma is extremely rare. It has been reported in diabetic patients whose hypoglycemic symptoms or high circulating insulin levels were ultimately explained by the discovery of an insulinoma (1, 2, 3, 4). Here, we describe a patient with a most unusual 24-yr history of a benign proinsulin-secreting insulinoma that initially caused classical hypoglycemic symptoms and then changed over time to the development of clinical diabetes.


    Case Report
 Top
 Introduction
 Case Report
 Discussion
 References
 
In 1976, a 47-yr-old white man without a prior history of endocrinopathy presented to the Clinical Center of the NIH for evaluation of a presumed insulinoma. He had no family history of endocrinopathy or diabetes. Eighteen months previously the patient had experienced an episode of hunger, diaphoresis, nervousness, and palpitations during a religious fast. These symptoms became more frequent over time and were typically relieved with food. Insulinoma was suspected on the basis of fasting hypoglycemia and inappropriately high insulin levels. In 1975, the patient underwent an exploratory laparotomy. However, the tumor could not be found, and a distal pancreatectomy and splenectomy were performed. Postoperatively, hyperinsulinemia and symptomatic hypoglycemia persisted. The patient was subsequently referred to the NIH.

On presentation to the NIH in 1976, his physical examination was unremarkable. An overnight fasting plasma glucose was 4.3 mmol/L (4.2–6.1 mmol/L), and insulin was 754 pmol/L (normal, 29–172 pmol/L). The insulin levels were measured with RIA, and the total immunoreactive insulin comprised of both insulin and proinsulin-like activity (5). The specific proinsulin-like activity was markedly elevated at 74% (normal, <20%) (5). Anti-insulin antibodies were negative. At the time, it was not possible to obtain a C-peptide level or a sulfonylurea screen. After 18 h of fasting, the patient’s plasma glucose decreased to 2.2 mmol/L with marked neuroglycopenic symptoms, whereas insulin levels ranged between 754 and 825 pmol/L (Table 1Go). A gastroduodenal arteriogram revealed an approximately 15-mm oval homogeneously staining density in the head of the pancreas (Fig. 1AGo). Right hepatic artery injection showed no evidence of hypervascular metastases.


View this table:
[in this window]
[in a new window]
 
Table 1. Eighteen-h fast in July 1998 and in January 1976

 


View larger version (89K):
[in this window]
[in a new window]
 
Figure 1. A selective gastroduodenal arteriogram (1975) showing a 15-mm diffusely enhancing islet cell tumor (A, arrows) in the inferior portion of the head of the pancreas. T-1 weighted (B) and gradient echo (C) magnetic resonance imaging scans (1998) show a 15-mm tumor (B and C, arrows) in the inferior portion of the pancreatic head, with imaging characteristics typical for a neuroendocrine tumor (low signal intensity on T-1-weighted images and bright signal on gradient echo images). Contrast-enhanced computerized tomography demonstrated a hypervascular tumor at the same site. A, Superior mesenteric artery; V, superior mesenteric vein; D, second duodenum.

 
The patient was advised to undergo a second laparotomy for the removal of the insulinoma. However, he refused this operation because he could not be assured that a total pancreatectomy could be avoided. He was well informed and intelligent and elected medical therapy. Accordingly, he received diazoxide 100–300 mg per day, from 1976 to 1995. In 1995, symptomatic hyperglycemia developed (Fig. 2Go). The diazoxide was discontinued. Although his diet and weight remained stable over the following 3 yr (body mass index, 25.4 kg/m2), his fasting plasma glucose values ranged between 8.3 and 13.9 mmol/L off diazoxide. HbA1c was 9.3% (normal, <6.2%) in March 1998.



View larger version (23K):
[in this window]
[in a new window]
 
Figure 2. Change of plasma glucose concentrations between 1975 and 1999. The diagnosis of insulinoma was made in 1975, and the patient was treated with diazoxide (D) after he refused surgery. Plasma glucose levels were markedly increased after 1991, and the diagnosis of type 2 diabetes was made in 1998. Treatment with metformin (M) was initiated.

 
In July 1998, the patient was readmitted to the NIH Clinical Center for follow-up. His physical examination did not reveal hypertension, exogenous obesity (body mass index, 25.5 kg/m2), or acanthosis nigricans. His fasting biochemical profile was as follows: triglycerides, 3.2 mmol/L; total cholesterol, 4.0 mmol/L; fasting plasma glucose level, 12.7 mmol/L; fasting insulin level, 423 pmol/L; fasting C-peptide level, 2200 pmol/L (normal, 170–900 pmol/L); fasting proinsulin level, 1000 pmol/L; and HbAlc, 9.7%. During a 5-h oral glucose tolerance test, levels of 2-h glucose and insulin were 15.1 mmol/L and 373 pmol/L, respectively. There was no significant insulin release with the oral glucose load, and the patient did not develop hypoglycemia during the 5-h test. Insulin was determined by an immunoassay using reagents provided by Abbott Imx Instrument (Abbott Park, IL; normal range: 35–145 pmol/L). The patient fasted for 18 h without symptoms of hypoglycemia (Table 1Go). During this fast, his insulin level decreased to 151 pmol/L; plasma glucose was 4.5 mmol/L, and proinsulin was 618 pmol/mL (normal, <22 pmol/mL). Plasma C-peptide levels decreased from 4400 pmol/L to 2200 pmol/L. Computed tomographic and magnetic resonance imaging studies of the pancreatic head showed a region of enhancement measuring approximately 15 mm that corresponded to the vascular tumor in the head of the pancreas, previously seen on the arteriogram (Fig. 1Go, b and c). Following treatment with 500 mg twice daily metformin therapy for 6 months, HbA1c was still 9.1% (normal, <6.2%) with a fasting plasma glucose level of 7.8 mmol/L and a fasting insulin level of 567 pmol/L. The dose of metformin was increased to 1 g twice daily.


    Discussion
 Top
 Introduction
 Case Report
 Discussion
 References
 
At age 45 yr, the patient presented with typical features of insulinoma, including hypoglycemia associated with marked neuroglycopenic symptoms, inappropriately high levels of plasma insulin and proinsulin, and radiographic findings consistent with an islet cell tumor of the pancreas. Twenty-four yr later, the patient has similar radiographic and biochemical findings but is now hyperglycemic, requiring treatment for diabetes. We have considered the possibility that the patient had a nonfunctional tumor of the pancreas and some other cause for the hypoglycemia. However, the continued presence of hyperinsulinemia and hyperproinsulinemia makes this highly unlikely.

High circulating levels of proinsulin and the net metabolic balance of hyperglycemia clinically resembles familial hyperproinsulinemia. Familial hyperproinsulinemia is characterized by normal or elevated blood glucose concentrations (6). Patients with this entity do not become hypoglycemic, unless some other process supervenes. Although circulating proinsulin has only approximately 20% the bioactivity of insulin, its failure to be suppressed by decreasing glucose concentrations during fasting results in hypoglycemia in states of increased metabolic demand or prolonged fasting (6). In this patient, 25 yr after the diagnosis of the insulinoma, the net metabolic balance results in hyperglycemia despite clear biochemical evidence of insulinoma with typical symptoms at the time of initial diagnosis. The mechanism of this evolution from insulin-induced hypoglycemia seen 25 yr ago to overt diabetes seen now is not completely clear.

It is possible that this patient now has two independent conditions (i.e. insulinoma and type 2 diabetes). A more likely explanation, however, is that production of proinsulin by the tumor coupled with suppression of endogenous insulin production by diazoxide contributes to hyperglycemia. This phenomenon is similar to hyperglycemia that occurs immediately after successful removal of an insulinoma and is thought to be due to prolonged suppression of endogenous insulin by hypoglycemia and/or hyperinsulinemia (7). In conclusion, this case provided a unique opportunity to observe the natural history of a proinsulin-secreting insulinoma without surgical resection. The transition from symptomatic hypoglycemia to clinical diabetes was unanticipated. We must reemphasize, again, that the decision made by the patient not to undergo further surgery is not to be recommended because of the potential dangers of hypoglycemia and/or malignancy.

Received January 26, 2000.

Revised May 8, 2000.

Revised June 19, 2000.

Accepted June 27, 2000.


    References
 Top
 Introduction
 Case Report
 Discussion
 References
 

  1. Gittler RD, Zucker R, Eisinger R, Stoller N. 1958 Amelioration of diabetes mellitus by an insulinoma. N Engl J Med. 258:932–935.[Medline]
  2. Knight PO. 1967 Insulinoma and generalized islet cell hyperplasia in a patient with diabetes mellitus. South Med J. 60:119–123.[Medline]
  3. Kane LA, Grant CS, Nippoldt TB, Service FJ. 1993 Insulinoma in a patient with NIDDM. Diabetes Care. 16:1298–1300.[Abstract]
  4. Wildbrett J, Nagel M, Theissig F, et al. 1999 An unusual picture of insulinoma in type-2 diabetes mellitus and morbid obesity. Dtsch Med Wochenschr. 124:248–252.[Medline]
  5. Gorden P, Skarulis MC, Roach P, et al. 1995 Plasma proinsulin-like component in insulinoma: a 25-year experience. J Clin Endocrinol Metab. 80:2884–2887.[Medline]
  6. Gruppuso PA, Gorden P, Kahn CR, et al. 1984 Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin. N Engl J Med. 311:629–634.[Abstract]
  7. Doherty GM, Doppman JL, Shawker TH, et al. 1991 Results of a prospective strategy to diagnose, localize, and resect insulinomas. Surgery. 110:989–996; discussion 996–997.[Medline]