Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.

Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.

Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

AIM: Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans. METHODS: This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am. RESULTS: Twenty-two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P = .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P = .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion. CONCLUSION: We found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.

Estimated plasma stearoyl co-A desaturase-1 activity and risk of incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVE: Evidence from pre-clinical studies suggests inhibition of stearoyl co-A desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study. METHODS: In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes. RESULTS: During follow-up (mean 8.0±SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition - only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05). CONCLUSIONS: In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.

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.

Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal preoperative glucose metabolism.

OBJECTIVE: Hemipancreatectomy (HPx) for the purpose of organ donation has been associated with a 25% risk of developing abnormal glucose tolerance or diabetes in the year after surgery. Since 1997, the University of Minnesota has imposed criteria to prevent potential donors with clinical features associated with an increased diabetes risk from undergoing HPx. We recently assessed glucose tolerance in hemipancreatectomized donors selected since the adoption of the new criteria to determine whether the risk of developing abnormal glucose tolerance was reduced below the 25% rate previously demonstrated. RESEARCH DESIGN AND METHODS: Individuals who underwent HPx for the purpose of pancreas donation between 1997 and 2003 were contacted and interviewed about their health status. Those not taking diabetes medications were invited to undergo an assessment of their glucose tolerance. RESULTS: Successful contact was made with 15 of 21 donors who underwent HPx during this period. Two donors reported use of oral diabetic medications and were not studied further. Of the remaining 13, 2 had impaired fasting glucose (fasting blood glucose 100-125 mg/dl), 1 had impaired glucose tolerance (2-h postglucose load blood glucose 140-199 mg/dl), and 3 displayed both. One donor met the diagnostic criteria for diabetes. Six donors had normal glucose values. CONCLUSIONS: Despite the use of stringent criteria to exclude those at risk for developing abnormalities in glucose metabolism, 43% of healthy humans who underwent HPx between 1997 and 2003 have impaired fasting glucose, impaired glucose tolerance, or diabetes on follow-up. The current preoperative criteria are insufficient to predict those who will develop abnormal glucose metabolism after HPx.

Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide.

We report a case of severe hypoglycemia occurring in a 35-yr-old woman, 6 yr after pancreas transplantation for type 1 diabetes mellitus. Extensive preoperative and intraoperative exploration failed to disclose the presence of a focal adenomatous lesion. Partial allograft pancreatectomy was performed initially, but it failed to control the hypoglycemic symptoms, leading to complete removal of the pancreas allograft. Histopathological examination of the resected pancreas allograft showed the presence of nesidioblastosis, characterized by foci of islet cells budding off ducts, accompanied by an increase in the number of islets, numerous small intralobular islet cell aggregates, and nesidiodysplasia (large, hyperchromatic islet cell nuclei). Islet neogenesis-associated protein-positive islets and ducts were seen by immunofluorescence. Insulin-positive islets ranged from very small to large, with isolated insulin-positive cells diffusely scattered, consistent with islet neogenesis. Very little glucagon staining was identified. Reported cases of adult nesidioblastosis are reviewed. The significance of nesidioblastosis in the context of pancreas transplantation and possible mechanisms of posttransplant hypoglycemia are discussed.

Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients.

BACKGROUND: Healthy human volunteers occasionally elect to undergo surgical removal of the distal half of their pancreas for donation to a relative with type 1 diabetes. This provides the unusual opportunity to study segments of the same pancreas in two markedly different environments, i.e., the normal one of the donor and the unusual one of the ectopically transplanted recipient who is receiving immunosuppressant drugs that can diminish insulin secretion and cause insulin resistance. METHODS: We studied eight donor/recipient pairs 9 to 18 years after the original surgery to assess the hypothesis that beta-cell mass is the primary determinant of glucose homeostasis. We measured levels of fasting glucose and hemoglobin A1c, intravenous glucose disappearance rates, acute insulin and C-peptide responses, and beta-cell secretory reserve. RESULTS: Comparisons of the mean data between the two groups revealed no significant differences in fasting plasma glucose, hemoglobin A1c, fasting insulin or C-peptide, acute insulin or C-peptide responses to arginine and to glucose, or beta-cell secretory reserve. Eight patients were obese; this subgroup contained all patients who developed mild diabetes (four donors and two recipients). CONCLUSION: The within-pairs metabolic outcomes support the primacy of pancreatic mass in determining glucose homeostasis, but the discordancy within pairs for developing postoperative diabetes implicates variables, especially obesity, as important secondary determinants in the risk of developing diabetes in donors and recipients. Our data suggest that obesity should be a contraindication to donation of pancreatic segments and that donors should assiduously avoid becoming obese.