Glucose clamps with the Biostator: a critical reappraisal.
ABSTRACT The Biostator makes it possible to perform glucose clamp experiments almost automatically. Thus, blood glucose concentrations can be maintained at (or close to) a target level with substantially less effort than with the manual clamp technique. The automatisation also avoids a potential bias on the part of the investigator. However, as with the non-automated manual clamp technique, blood glucose concentrations do not remain exactly at the target value, as they show a considerable scatter around the target value. This scatter is generated by the time constants of the Biostator, i.e. the whole closed-loop system, and the autoregressive properties of the glucose clamp algorithm used. In order to describe the quality of glucose clamps over time more precisely, "cumulative sums" as an alternative to the usual coefficient of variation can be used. Practical work with the Biostator is burdened with technical difficulties and considerable costs in comparison to the manual clamp technique. Deficits concerning data storage and presentation capability of the Biostator have been overcome by an appropriate programme for an external computer. The use of the Biostator for the glucose clamp technique is not mandatory, but, the use of this machine makes it possible to perform glucose clamp studies under standardised and reproducible conditions.
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ABSTRACT: The central objective of diabetes research and management is to restore the deficient secretion of insulin, thereby restoring a state of euglycemia and minimizing short- and long-term risks associated with poor glucose control. The development of the artificial pancreas seeks to imitate the action of the pancreatic beta cell by employing closed-loop control to respond to glycemic excursions by appropriately infusing appropriate amounts of insulin. This article examines progress towards implementing an artificial pancreas in the context of the pancreatic islet as the ideal model for controlling blood glucose. Physiologic insulin secretion will form our foundation for considering the technical design elements relevant to electromechanically imitating the beta cell. The most recent clinical trials using closed-loop control are reviewed and this modality is compared to other curative approaches including islet cell transplantation and preservation. Finally, the potential of the artificial pancreas as a method to adequately reestablish euglycemia is considered.Organogenesis 01/2011; 7(1):32-41. · 2.28 Impact Factor
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ABSTRACT: Because of the slow pharmacokinetics of subcutaneous (SC) insulin, avoiding postprandial hyperglycemia has been a major challenge for an artificial pancreas (AP) using SC insulin without a meal announcement. A semiautomated AP with Technosphere® Insulin (TI; MannKind Corporation, Valencia, CA) was designed to combine pulmonary and SC insulin. Manual inhalation of 10 U ultrafast-absorbing TI at mealtime delivers the first, or cephalic, phase of insulin, and an SC insulin pump controlled by zone model predictive controller delivers second-phase and basal insulin. This AP design was evaluated on 100 in silico subjects from the University of Virginia/Padova metabolic simulator using a protocol of two 50 g carbohydrate (CHO) meals and two 15 g CHO snacks. Simulation analysis shows that the semiautomated AP with TI provides 32% and 16% more time in the controller target zone (80-140 mg/dl) during the 4 h postprandial period, with 39 and 20 mg/dl lower postprandial blood glucose peak on average than the pure feedback AP and the AP with manual feed-forward SC bolus, respectively. No severe hypoglycemia (<50 mg/dl) was observed in any cases. The semiautomated AP with TI provides maximum time in the clinically accepted region when compared with pure feedback AP and AP with manual feed-forward SC bolus. Furthermore, the semiautomated AP with TI provides a flexible operation (optional TI inhalation) with minimal user interaction, where the controller design can be tailored to specific user needs and abilities to interact with the device.Journal of diabetes science and technology 01/2013; 7(1):215-26.
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ABSTRACT: BACKGROUND & AIMS: Obeticholic acid (OCA, INT-747, 6α-ethyl-chenodeoxycholic acid) is a semi-synthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor (FXR)-a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS: We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Patients were randomly assigned to groups given placebo (n=17), 25 mg OCA (n=15), or 50 mg OCA (n=13) once daily for 6 weeks. A 2-stage hyperinsulinemic euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4, a BA precursor), endogenous BAs, and markers of liver fibrosis. RESULTS: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group given 25 mg OCA (P=.019) and 20.1% from baseline in the group given 50 mg OCA (P=.060). In combined OCA groups, insulin sensitivity increased by 24.5% (P=.011), whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of LDL cholesterol and FGF19, associated with decreased levels of C4 and endogenous BA, indicating activation of FXR. Markers of liver fibrosis decreased significantly in the 25 mg OCA group. Adverse experiences were similar among groups. CONCLUSIONS: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes an NAFLD. Longer, larger studies are warranted. ClinicalTrials.gov: NCT00501592.Gastroenterology 05/2013; · 12.82 Impact Factor