Selective Arterial Calcium Stimulation With Hepatic Venous Sampling in Immune-Mediated Hypoglycemia.

The purpose of the current study was to review the biochemical results of selective arterial calcium stimulation (SACST) with hepatic venous sampling in patients with immune-mediated hyperinsulinemic hypoglycemia. A retrospective review was undertaken of four patients with immune-mediated hyperinsulinemic hypoglycemia who underwent SACST with hepatic venous sampling from January 1996 to March 2014. Baseline systemic arterial and hepatic venous insulin concentrations (uIU/mL) were compared, and the absolute and relative-fold increase in hepatic venous insulin concentration after calcium stimulation was calculated. Baseline systemic arterial and hepatic venous insulin concentrations were elevated in all vessels sampled (range, 95 to 1704 uIU/mL), and there was no increase in the absolute or relative (1.0- to 1.3-fold) hepatic venous insulin concentration after calcium injection into any vessel. These data suggest that there are distinct biochemical responses to SACST in patients with immune-mediated hyperinsulinemic hypoglycemia compared with patients with endogenous, pancreatic-mediated hypoglycemia, such as insulinoma or nesidioblastosis.

Selective Arterial Calcium Stimulation with Hepatic Venous Sampling in Patients with Recurrent Endogenous Hyperinsulinemic Hypoglycemia and Metastatic Insulinoma: Evaluation in Five Patients.

Selective arterial calcium stimulation (SACST) with hepatic venous sampling was performed in 5 patients (3 female, 2 male; age range, 53-73 y) with recurrent endogenous hyperinsulinemic hypoglycemia caused by metastatic insulinoma between January 2004 and December 2014. The biochemical results of SACST confirmed functional hepatic metastases alone (n = 3), peripancreatic lymph-node and hepatic metastases (n = 1), and occult insulinoma in the pancreatic bed (n = 1), thereby helping to guide management. SACST may be useful to determine the extent of functional metastatic insulinoma, particularly within the liver, and may provide clinicians with additional information to help guide the multidisciplinary management of patients with recurrent endogenous hyperinsulinemic hypoglycemia.

Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study.

OBJECTIVE: During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS: Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS: One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91-1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS: Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.

Association of Glycemic Variability in Type 1 Diabetes With Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial.

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated the beneficial effects of intensive versus conventional therapy on the development and progression of microvascular complications of type 1 diabetes. These beneficial effects were almost completely explained by the difference between groups in the levels of HbA1c, which in turn were associated with the risk of these complications. We assessed the association of glucose variability within and between quarterly 7-point glucose profiles with the development and progression of retinopathy, nephropathy, and cardiovascular autonomic neuropathy during the DCCT. RESEARCH DESIGN AND METHODS: Measures of variability included the within-day and updated mean (over time) of the SD, mean amplitude of glycemic excursions (MAGE), and M-value, and the longitudinal within-day, between-day, and total variances. Imputation methods filled in the 16.3% of expected glucose values that were missing. RESULTS: Cox proportional hazards models assessed the association of each measure of glycemic variation, as a time-dependent covariate, with the risk of retinopathy and nephropathy, and a longitudinal logistic regression model did likewise for cardiovascular autonomic neuropathy. Adjusted for mean blood glucose, no measure of within-day variability was associated with any outcome. Only the longitudinal mean M-value (over time) was significantly associated with microalbuminuria when adjusted for the longitudinal mean blood glucose and corrected for multiple tests using the Holm procedure. CONCLUSIONS: Overall, within-day glycemic variability, as determined from quarterly glucose profiles, does not play an apparent role in the development of microvascular complications beyond the influence of the mean glucose.

Selective Arterial Calcium Stimulation With Hepatic Venous Sampling Differentiates Insulinoma From Nesidioblastosis.

CONTEXT: In adult patients with endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging, insulinoma and non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) resulting from diffuse nesidioblastosis must be considered in the differential diagnosis. It is not known whether the biochemical results of selective arterial calcium stimulation (SACST) with hepatic venous sampling can differentiate insulinoma from diffuse nesidioblastosis. OBJECTIVE: To determine the specificity of SACST with hepatic venous sampling in differentiating insulinoma from diffuse nesidioblastosis. DESIGN: Retrospective review (January 1996 to March 2014). SETTING: Tertiary referral center. PATIENTS OR OTHER PARTICIPANTS: A total of 116 patients with biochemical evidence of endogenous hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging who were subsequently shown at surgery to have insulinoma (n = 42) or nesidioblastosis (n = 74) after undergoing SACST with hepatic venous sampling. INTERVENTION(S): SACST with hepatic venous sampling before pancreatic exploration. MAIN OUTCOME MEASURE(S): Receiver operating characteristic curves were generated from the biochemical results of SACST to determine the specificity of the maximum hepatic venous insulin concentration (mHVI) and the relative-fold increase in hepatic venous insulin concentration (rHVI) over baseline after calcium injection from the dominant artery in differentiating insulinoma from nesidioblastosis. RESULTS: The mHVI (21.5-fold; P < .001) and rHVI (3.9-fold; P < .001) were significantly higher in the insulinoma group compared to the nesidioblastosis group. The areas under the receiver operating characteristic curve for mHVI and rHVI were excellent (0.94; P < .0001) and good (0.83; P < .0001), respectively, for differentiating insulinoma from nesidioblastosis. mHVI cutoffs of > 91.5 and > 263.5 µIU/mL were 95 and 100% specific for insulinoma, respectively. A 19-fold increase in rHVI over baseline was 99% specific for insulinoma. CONCLUSIONS: These data suggest that the mHVI and rHVI at SACST may be useful in differentiating insulinoma from nesidioblastosis with high specificity in patients with hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging.

Impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation with hepatic venous sampling for preoperative localization of occult insulinoma.

BACKGROUND: To determine the impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation of selective arterial calcium stimulation (SACST) with hepatic venous sampling for preoperative localization of occult insulinoma. METHODS: An institutional review board-approved retrospective review was undertaken of 42 patients with surgically confirmed, occult insulinoma who underwent SACST from January 1996 to March 2014. Location of the insulinoma was predicted initially based on the biochemical results of SACST alone according to Doppman's criteria. Pancreatic arteriograms were reviewed blinded to the biochemical results and the regional perfusion of each artery assessed. The anatomic and perfusion data were combined with the biochemical results to make a second prediction and compared with the surgical findings. RESULTS: The biochemical results were positive in 1, 2, and 3 arterial distributions in 73.8%, 21.4%, and 4.8% of patients, respectively. The celiac trunk and superior mesenteric artery (SMA) anatomy were aberrant in 38.1% and 35.7% of patients, respectively. Clinically significant variations included dorsal pancreatic artery replaced to SMA (21.4%) and celiac stenosis (4.8%). Significant variation and overlap in regional pancreatic perfusion was observed, particularly for the SMA. Sensitivity for insulinoma localization was 54.8% (diagnostic arteriography), 73.8% (biochemical data), 88.1% (biochemical, anatomic, perfusion data), and 92.8% (arteriographic, biochemical, anatomic, perfusion data). CONCLUSION: Careful review of the pancreatic arterial anatomy and regional perfusion is critical for correct interpretation of the biochemical results of SACST and improves the sensitivity of localization for occult insulinoma, particularly in the presence of pancreatic arterial variants or overlap in regional perfusion.

Glucose variability.

The proposed contribution of glucose variability to the development of the complications of diabetes beyond that of glycemic exposure is supported by reports that oxidative stress, the putative mediator of such complications, is greater for intermittent as opposed to sustained hyperglycemia. Variability of glycemia in ambulatory conditions defined as the deviation from steady state is a phenomenon of normal physiology. Comprehensive recording of glycemia is required for the generation of any measurement of glucose variability. To avoid distortion of variability to that of glycemic exposure, its calculation should be devoid of a time component.

Outcomes and quality of life after partial pancreatectomy for noninsulinoma pancreatogenous hypoglycemia from diffuse islet cell disease.

BACKGROUND: Noninsulinoma pancreatogenous hypoglycemia (NIPH) is a rare cause of hypoglycemia, especially affecting postbariatric surgery patients, related to excessive insulin secretion. Partial pancreatectomy controls hypoglycemia in the early postoperative period; however, multiple patients have experienced symptomatic relapse. The study goal was to assess frequency and severity of recurrent symptoms in operated patients. METHODS: All patients who underwent pancreatic resection for NIPH at Mayo Clinic from January 1996 through December 2008 were reviewed for demographics, preoperative testing, operative and postoperative details. Data from patient records, mail survey, European Quality of Life Survey (EQ-5D), and Fear of Hypoglycemia Scale (FOHS) were used to assess outcome. RESULTS: Seventy-five patients underwent pancreatic resection for NIPH (5 dead, 1 incarcerated). 48 patients (70%) completed the survey; mean follow-up, 53 months. Median time to recurrent symptoms was 16 months in 41 patients (87%). Despite symptom recurrence, 36 patients (75%) reported overall improvement in symptoms and quality of life (QOL); median EQ-5D health scores increased from 40 to 75 out of 100 (P < .001). Moreover, they reported marked reduction in psychologic stress and hypoglycemic symptoms with greater than 50% decrease in FOHS overall, worry, and behavioral median scores (P < .001). Overall, half of the patients were classified as highly/moderately surgically successful, whereas the other half was minimally successful or surgical failures. CONCLUSION: Although nearly 90% of NIPH patients reported recurrent symptoms suggestive of hypoglycemia, a majority reported improvements in QOL and marked reduction in other symptoms after pancreatic resection. Nevertheless, 25% of patients experienced no benefit from partial pancreatectomy.

Hypoglycaemia following upper gastrointestinal surgery: case report and review of the literature.

BACKGROUND: Hyperinsulinemic hypoglycemia is relatively recently recognized in persons undergoing bariatric surgery although knowledge and experience with this condition may not be commensurate with the number of such procedures being performed globally. This paper presents a novel case as an example of how such patients may present and how they may be investigated. CASE PRESENTATION: A 69-year-old man was assessed 3 months post-fundoplication surgery for postprandial hypoglycaemia with neuroglycopenia that became progressively severe. A 72-h fast failed to show hypoglycaemia. During a clinic visit, the patient became confused and had a low plasma glucose, high plasma insulin, and high plasma C-peptide; symptoms were relieved with glucose. No tumours were visualized on CT, MRI, or endoscopic ultrasound. A total body Indium111-octreotide scan was negative. Selective arterial calcium stimulation showed a high insulin gradient in the splenic and superior mesenteric arteries, suggesting diffuse pancreatic beta cell hyperplasia. The patient declined pancreatic resection and recurrent symptomatic hypoglycaemia was successfully prevented with low dose octreotide. CONCLUSIONS: Although increasingly recognized following bariatric surgery, this is the first reported development of NIPHS (non-insulinoma pancreatogenous hypoglycemia syndrome) following fundoplication surgery, as well as the first documented use of octreotide in post-operative NIPHS. Medical management may be an alternative to surgery for patients with this rare condition.

Deletion of 8q24 in an adult with mild dysmorphic features, developmental delay, and ketotic hypoglycemia.

We present a 56-year-old female with a history of carbohydrate intolerance and ketotic hypoglycemia, dysmorphic features, mild developmental delay, lymphedema, altered pain sensation, and frequent fractures, who was found to have a heterozygous 8.09 Mb deletion of chromosome 8q24.11q24.13 containing more than 39 genes, as well as a duplication of 20q11.23 containing one gene. The deleted region overlaps that of two previously reported patients, who share a subset of clinical characteristics with the patient described here. Some of this patient's clinical features are consistent with the loss of genes in the deleted region. The diagnostic work-up of this patient clearly demonstrates the evolution of genetic testing techniques.

Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007.

OBJECTIVE: The objective of the study was to assess changes in the presentation and diagnostic and radiological evaluation of patients with surgically confirmed insulinoma at the Mayo Clinic 1987-2007. METHODS: A retrospective analysis of patients with insulinoma was conducted. Patients with prior gastric bypass were excluded. RESULTS: A total of 237 patients [135 women (57%)] were identified. Hypoglycemia was reported solely in the fasting state in 73%, the fasting and postprandial state in 21%, and exclusively postprandially in 6%. There was a predominance of men in the postprandial symptom group. Considering the period of study by quartile, outpatient evaluation increased from 35 to 83% and successful preoperative localization improved from 74 to 100% comparing the first to the fourth quartiles. Although the rates of localization by noninvasive techniques remained static at approximately 75%, the addition of invasive modalities has resulted in successful preoperative localization in all patients in the past 10 yr. The sensitivity and specificity of the established diagnostic criteria using insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose response to iv glucagon were greater than 90% and greater than 70%, respectively. CONCLUSIONS: Although fasting hypoglycemia is characteristic of patients with insulinoma, postprandial symptoms have been reported with increasing, albeit low, frequency. Trends in the evaluation and preoperative management include a shift to outpatient diagnostic testing, an emphasis on successful preoperative localization to avoid blind pancreatic exploration, and a validation of the diagnostic criteria for hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression.

Hypoglycemia secondary to nesidioblastosis is rare in adults, and the pathogenesis of this condition is unknown. To determine factors leading to nesidioblastosis in adults, we analyzed 36 cases of nesidioblastosis including 27 cases of postgastric bypass nesidioblastosis and 9 cases of idiopathic nesidioblastosis in adults by immunohistochemistry using antibodies to insulin-like growth factor 1, insulin-like growth factor 2 (IGF2), insulin-like growth factor one receptor-alpha epidermal growth factor receptor, transforming growth factor-beta1 and 2, and transforming growth factor-beta receptor type 3. Fifty-two surgically excised pancreatic specimens from patients with benign exocrine tumors and no evidence of hypoglycemia were used as controls. There was increased IGF2, insulin-like growth factor receptor 1 receptor-alpha and transforming growth factor-beta receptor 3 expression in islets from nesidioblastosis patients compared to controls. Peliosis-type vascular ectasia was more common in nesidioblastosis patients compared to controls. These findings suggest that increased production of growth factors and growth factor receptors may contribute to the development of nesidioblastosis in adults.

Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.

OBJECTIVE: The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus. EVIDENCE: Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle). CONCLUSIONS: We recommend evaluation and management of hypoglycemia only in patients in whom Whipple's triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.

Influence of glycemic variables on hemoglobin A1c.

OBJECTIVE: To assess the influences of a wide variety of glucose variables on hemoglobin A1c (A1C). METHODS: The Diabetes Control and Complications Trial database, restricted to volunteers whose 7-point daily capillary glucose profiles were complete in >or=80% of quarterly collections and who were in the study for >or=4 years, was used for analysis. Regression analyses were done to develop an equation for estimating A1C based on concurrent and prior mean blood glucose (MBG) values. The multivariate coefficient of determination (R2) was calculated for MBG, mean postprandial blood glucose, mean preprandial blood glucose, digestive glycemia, interdigestive glycemia, individual time points of the 7-point glucose profile, range of blood glucose, SD of blood glucose, M-value, and mean amplitude of glycemic excursions in relationship to A1C. By using regression analysis, the correlation between A1C and MBG within each study subject was determined. RESULTS: The most accurate prediction of A1C was obtained from the concurrent MBG. With use of univariate analysis, all glucose variables correlated significantly with concurrent A1C, the strongest correlation occurring with MBG. In multivariate analysis, the primary predictor of A1C was MBG; all other glucose variables added nothing to the models. Within-subject correlations between MBG and A1C showed considerable variation. CONCLUSION: A1C correlates best with MBG derived from 7-point-daily capillary glucose profiles. The influences of glucose measured at specific time points during the day or various measures of glucose variability on A1C are less than that of MBG. Within the limitations of the intermittent glucose determinations, wide variations in the relationship of MBG to A1C among and within patients with type 1 diabetes remain unexplained.