Preoperative detection of pancreatic insulinomas on multiphasic helical CT.

OBJECTIVE: The objective was to analyze enhancement characteristics of insulinomas and to determine the ability of multiphase CT to localize these tumors. MATERIALS AND METHODS: Prospective interpretations of multiphase helical CT scans were reviewed in 30 patients who had insulinomas resected over a 5-year period. CT scans were retrospectively reviewed to determine enhancement characteristics, tumor conspicuity in each phase of enhancement, and potential causes for false-negative findings. RESULTS: Sixty-three percent (19/30) of tumors were identified on CT prospectively. An additional six tumors were visualized in retrospect, allowing characterization of 25 (83%) of 30 tumors. Most tumors were hyperdense on at least one phase (n = 19), three tumors were hypoattenuating, and three were isodense and pedunculated. Insulinomas were most conspicuous on the early phase in 15 patients and in the portal venous phase in three. All tumors that underwent pancreatic phase imaging were seen (13/13), whereas three of 18 arterial and six of 25 portal venous phase findings were inconclusive for tumor. In the six examinations with false-negative findings in which the tumor could be seen in retrospect, two tumors were isodense and pedunculated, three were in close proximity to vessels, and one had a cystic appearance. CONCLUSION: Multiphasic CT has a moderate sensitivity in the detection of insulinomas. Most tumors are more conspicuous on the earlier phases of enhancement. The pancreatic phase may be more useful than the arterial phase. Potential sources of false-negative results include tumors adjacent to vessels, pedunculated morphology, or nonhyperattenuating lesions.

Insulinoma in chronic renal failure: a case report.

The diagnosis of insulinoma depends on the fulfillment of well-established criteria during the 72-h fast. However, these criteria rely on normal renal function. Spontaneous hypoglycemia that is not attributable to insulinoma may occur in persons with renal failure. We describe herein a patient with renal impairment who had undergone renal transplant and had a 20-yr history of hypoglycemic symptoms and successful resection of insulinoma. Although the results of a 72-h fast were consistent with endogenous hyperinsulinemia, their interpretation was complicated in the presence of renal impairment. Fortunately, the identification of the tumor, by endoscopic ultrasonograph, led to a correct diagnosis. This case seems to be the second report of a patient with insulinoma with concomitant renal failure.

The relation of glycaemia to the risk of development and progression of retinopathy in the Diabetic Control and Complications Trial.

AIMS/HYPOTHESIS: We have assessed the relation between the quarterly capillary glucose profile and the risk of the development and progression of retinopathy in the DCCT. METHODS: Seven point (preprandial and 90-min postprandial for each meal and bedtime) capillary glucose data were analysed from volunteers whose collections were complete in 80 %, or more, of quarterly periods and who were in the study longer than 4 years (n = 296, conventional therapy; n = 269, intensive therapy). The study cohort differed from excluded patients in having more women and lower HbA(1c) at baseline and fewer adolescents, older age and lower baseline mean blood glucose in the intensive therapy group. RESULTS: Univariate analysis showed significant (p < 0.01) associations to sustained 3-step change in retinopathy of each updated glycaemic parameter: mean blood glucose, mean preprandial glucose, mean postprandial glucose, each preprandial, postprandial and bedtime glucose; range glucose, standard deviation glucose; M-value of Schlichtkrull and mean amplitude of glycaemic excursions, albeit with relatively small hazard ratios. Multivariate analyses showed updated mean blood glucose to be the primary risk factor (p < 0.001) with a weak contribution of mean amplitude of glycaemic excursions at baseline (p < 0.005); no other variables added significantly to the model. The association between updated mean blood glucose and risk for retinopathy was nonlinear: risk progressively increased above updated mean blood glucose of 8.3 mmol/l. A gradient of risk could not be determined below this level because events were few. CONCLUSION/INTERPRETATION: Within the limitations provided by quarterly 7-point capillary glucose measurements as an expression of overall glycaemic behaviour, the major risk for progression of retinopathy is conveyed by updated mean blood glucose especially above 8.3 mmol/l.

Noninsulinoma pancreatogenous hypoglycemia syndrome: an update in 10 surgically treated patients.

BACKGROUND: Neuroglycopenia from endogenous hyperinsulinism usually is caused by insulinomas in adults. We recently reported a novel hypoglycemic disorder in 5 patients (patients 1 to 5) with postprandial neuroglycopenia, negative 72-hour fasts, negative perioperative imaging studies, but positive calcium stimulation tests and islet hypertrophy and nesidioblastosis in the gradient-guided resected pancreata. METHODS: In this report we compare our experience with 5 additional patients (patients 6 to 10) with this syndrome to that in the original report. RESULTS: The clinical features of patients 6 to 10 were similar to those of patients 1 to 5. Each had positive calcium stimulation testing that guided the extent of the distal pancreatectomy and histologic evidence of islet cell hypertrophy or nesidioblastosis. All 10 patients are alive from 9 to 50 months after operation, 1 of whom had no amelioration of neuroglycopenia. Minor perioperative complications occurred in 3 patients. One patient has experienced repeated bouts of acute pancreatitis, pseudocyst formation, and exocrine insufficiency. CONCLUSIONS: We have identified adult patients with severe, postprandial hyperinsulinemic hypoglycemia from diffuse islet cell disease, 80% of whom have been well palliated with surgery. The results in 7 men have been better than those in the 3 women for reasons that are not obvious.

Diagnostic approach to adults with hypoglycemic disorders.

Optimal conditions for confirming the presence and accurately diagnosing the type of hypoglycemic disorder occur at the time of a spontaneous spell. Otherwise, dynamic testing to generate conducive conditions should be conducted in any patient with a history of neuroglycopenic symptoms, regardless of relation to meal ingestion. Specific criteria regarding beta-cell polypeptide concentrations are required to establish hyperinsulinemia. Sulfonylureas in plasma should be measured with sensitive assays. In complex cases, the selective arterial calcium test may be a useful dynamic test.

Classification of hypoglycemic disorders.

The classification of symptoms of hypoglycemia, namely, reactive versus fasting, based on segregation by timing in relation to meals is no longer useful from a clinical point of view. Every patient with neuroglycopenic symptoms, regardless of relation to food ingestion, requires comprehensive evaluation. Identification of the possible cause of hypoglycemia and selection of diagnostic modalities are facilitated by considering whether the patient appears to be healthy (with or without compensated coexistent disease) or ill (with a disease known to have a proclivity to develop hypoglycemia, or is hospitalized). Medications may mediate hypoglycemia in anybody, whether they appear healthy or ill.

Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort.

OBJECTIVE: Chronic hyperglycemia relates to the occurrence of diabetic polyneuropathy (DPN), but has not yet been shown to relate to its overall severity In addition, the degree and duration of hyperglycemia, which measure of chronic hyperglycemia is most predictive of defined levels of severity of DPN, and which other putative risk factors are involved remain unknown. RESEARCH DESIGN AND METHODS: In a longitudinal study of 264 diabetic individuals in Rochester, MN, risk factors and other diabetic complications assessed at regular intervals during an average of approximately 7 years were tested for their association with a composite score of severity of DPN at the last examination. RESULTS: In multivariate analysis, diabetic retinopathy severity level (at last examination), mean ln(24-h proteinuria x duration of diabetes), and mean GHb were the main covariates for severity of DPN (R2 = 0.33). Excluding markers of microvessel and macrovessel disease, the independent risk factors were mean In(GHb x duration of diabetes), GHb, and type of diabetes (R2 = 0.23). CONCLUSIONS: We found that diabetic microvessel disease, chronic hyperglycemia exposure, and type of diabetes are associated with severity of DPN, and we believe these factors are implicated in its cause. Each of the five markers of microvessel disease was a strong covariate for severity of DPN. Mean GHb predicts severity of DPN better than duration of diabetes, and the latter predicts severity of DPN better than mean fasting plasma glucose. Knowing the severity of microvessel disease, the degree of chronic hyperglycemia exposure, and the type of diabetes provides useful information to evaluate whether a coexisting polyneuropathy and its severity is probably due to diabetes.

Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes.

In adults, endogenous hyperinsulinemic hypoglycemia is almost invariably due to insulinoma. In these patients with insulinoma, neuroglycopenic episodes exclusively after meal ingestion and negative 72-h fasts are extraordinarily rare. We describe five adults with neuroglycopenic episodes from hyperinsulinemic hypoglycemia within 4 h of meal ingestion and negative 72-h fasts. Each had negative transabdominal ultrasonography, spiral computed tomographic scanning, and celiac axis angiography of the pancreas. However, all showed positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction. At pancreatic exploration, no insulinoma was detected by intraoperative ultrasonography and complete mobilization and palpation of the pancreas. Moreover, the resected pancreata showed islet hypertrophy and nesidioblastosis, but no insulinoma. No definite disease-causing mutation was detected in Kir6.2 and SUR1 genes, which encode the subunits of the pancreatic ATP-sensitive potassium channel responsible for glucose-induced insulin secretion. Four patients who underwent gradient-guided partial pancreatectomy have been free of hypoglycemic symptoms for up to 3 yr follow-up; the other, who underwent a limited distal pancreatectomy, has had brief recurrence of symptoms. The unique clinical features and responses to dynamic testing in these adults with hyperinsulinemic hypoglycemia in the absence of insulinoma may constitute a new syndrome of postprandial hypoglycemia from diffuse beta-cell hyperfunction.

Glycated hemoglobin in insulinoma.

OBJECTIVE: To determine whether preoperative levels of glycated hemoglobin (GHb) are lower in patients with functioning insulinoma and, if so, whether a distinct separation of GHb values from those in control subjects might serve for diagnosis. METHODS: We examined preoperative GHb in consecutive patients (who had this measurement done) with surgically confirmed insulinoma for the period 1983 (when the current method became available for routine use) through 1996. Hemoglobin A(1) (HbA(1)) was measured by the Isolab Glyc-Affin Test System (normal range, 4 to 7%). We studied 64 patients with insulinoma (40 women and 24 men; median age, 47.5 years; age range, 21 to 79) and 38 control subjects (25 women and 13 men; median age, 42.5 years; age range, 20 to 83) considered not to have a hypoglycemic disorder on the basis of normal results of a supervised 72-hour fast. RESULTS: HbA(1) was significantly lower in patients with insulinoma (median, 4.7%; range, 2.7 to 6.9%) than in control subjects (median, 5.3%; range, 4.1 to 6.4%) (P<0.001, two-tailed rank sum test). Among 15 patients with insulinoma treated with diazoxide preoperatively, HbA(1) was higher (median, 4.8%; range, 4.2 to 6.9%) than in patients not treated with diazoxide (median, 4.6%; range, 2.7 to 5.7%), although the difference was not statistically significant (P = 0.08). CONCLUSION: Because of considerable overlap in HbA(1) values, no GHb value was diagnostic for insulinoma; however, 16 of 64 patients (25%) with insulinoma had HbA(1) values below the lowest value (4.1%) in control subjects. Thus, HbA(1) values less than 4.1% in patients with possible insulinoma are strongly indicative of that disorder.

Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study.

The quality of the epidemiological data on diabetic neuropathies remains poor for a variety of reasons. They include variability in 1) ascertainment of diabetes, 2) the clinical varieties of diabetic patients studied, 3) characterization of neurological dysfunction, 4) abnormal limits for neurological examinations and tests, 5) minimal criteria for neuropathy, 6) correct attribution of nondiabetic neurological disease, 7) correct attribution of type of neuropathy, 8) estimating neuropathy from use of multiple tests, and 9) estimating severity of polyneuropathy. We have tried to remedy these short-comings in the Rochester Diabetic Neuropathy Study (RDNS). It was not possible to adequately characterize and quantitate diabetic polyneuropathies using only one or two clinical or test abnormalities. To estimate severity of diabetic polyneuropathy, the results of the neurological examination and abnormalities of nerve conduction, quantitative sensory tests, and quantitative autonomic tests were combined into a composite score. One begins by scoring a standard test of neurological deficits (impairments) of the lower limbs (NIS[LL]) and adds to this transformed numbers for percentile abnormality of seven good functional tests. This NIS(LL)+7 tests score appears to provide a much more comprehensive and stable numeric score by which to diagnose and grade severity of diabetic polyneuropathy than does the use of individual clinical or test results. This test score should be useful as a measure of change in diabetic polyneuropathy for purposes of medical practice, epidemiology studies, and controlled clinical trials. The staging approach that we introduced previously continues to provide an important measure of overall severity of diabetic polyneuropathy, taking into account both symptoms and impairments.

Dermal interstitial glucose as an indicator of ambient glycemia.

OBJECTIVE: Using a novel minimally invasive (< or = 1.4 mm) technique to sample minuscule (0.5 microliter) amounts of dermal interstitial fluid (ISF), we assessed the accuracy of its glucose concentrations in predicting concurrently measured venous plasma and capillary plasma glucose concentrations. RESEARCH DESIGN AND METHODS: A total of 67 adult (37 male and 30 female) volunteers (57 with and 10 without diabetes) with venous plasma glucose levels from 1.6 to 28.4 mmol/l underwent forearm ISF, antecubetal venous, and fingertip capillary sampling. RESULTS: Rank correlations were 0.974 for ISF 1 vs. 2, 0.954 for ISF vs. venous, 0.935 for ISF vs. capillary, and 0.987 for venous vs. capillary. Median absolute differences were 0.53 mmol/l for ISF 1 vs. 2, 1.33 mmol/l for ISF vs. venous, 1.06 mmol/l for ISF vs. capillary, and 0.56 mmol/l for capillary vs. venous. Equations expressing ISF glucose as a function of venous and capillary glucose and equations expressing capillary glucose as a function of venous glucose had slopes of 0.995, 0.936, and 1.021, respectively (none significantly different from unity), and intercepts of 1.03 mmol/l (P = 0.024), 0.94 mmol/l (P = 0.131), and 0.56 mmol/l (P = 0.041), respectively. Error grid analysis of ISF vs. venous glucose and of capillary vs. venous glucose showed that 97% of the measurements fell within grids A and B. CONCLUSIONS: Dermal ISF sampling is a bloodless minimally invasive technique that provides a medium for glucose measurement, the concentrations of which closely reflect ambient glycemia to a degree comparable with that of capillary glucose measurements.

The classification of diabetes by clinical and C-peptide criteria. A prospective population-based study.

OBJECTIVE: To evaluate both the concordance in the classification of diabetes by clinical and C-peptide criteria and, prospectively, the consistency of the classification by C-peptide. RESEARCH DESIGN AND METHODS: Individuals with diabetes who were enlisted in the prospective epidemiological study of diabetic neuropathy (Rochester Diabetic Neuropathy Study [RDNS]) were classified clinically by National Diabetes Data Group (NDDG) criteria to IDDM and NIDDM at entry to the study. In addition, C-peptide response to 1 mg glucagon was measured at entry for the classification to IDDM (basal C-peptide, < 0.17 pmol/ml; increment above basal, < 0.07 pmol/ml) and NIDDM (all other responses) and for concordance with the clinical classification made. The consistency of the C-peptide response was assessed every 2 years for up to 8 years. RESULTS: Among 346 individuals with diabetes, 84 were classified as IDDM and 262 as NIDDM by clinical algorithm. COncordance with the C-peptide response occurred in 89% of the patients and remained consistent during 8 years of follow-up. Among the 37 patients with discordant clinical and C-peptide classification, those considered clinically to have NIDDM had a consistent IDDM C-peptide response during follow-up, and most of those considered to have IDDM clinically eventually showed an IDDM C-peptide response during follow-up. CONCLUSIONS: Clinical criteria for the classification of diabetes are highly correlated with the assessment of insulin secretory reserve. A small number of individuals considered to have NIDDM clinically or by C-peptide have or develop an IDDM peptide response.

Hypoglycemia.

The diagnosis of a hypoglycemic disorder requires a high level of suspicion, careful assessment of the patient for the presence of mediating drugs or predisposing illness, and, when indicated, methodic evaluation of the basis of well-defined diagnostic criteria. The diagnostic burden is heaviest for healthy-appearing persons with episodes of confirmed neuroglycopenia. The author's criteria for insulin mediation of hypoglycemia are plasma insulin of 6 microU/mL or higher (radioimmunoassay), C-peptide of 200 pmol/L or higher (ICMA), proinsulin of 5 pmol/L or higher (ICMA), beta OH butyrate of 2.7 mmol/L or lower, and generous (> or = 25 mg/dL) response of plasma glucose to intravenous glucagon administered when the patient is hypoglycemic. Sulfonylurea should be sought in the plasma of any hypoglycemic patient, especially by an assay which can detect the second generation of these drugs.