The Physiology of Insulin Clearance

In the 1950’s, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable

Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia

OBJECTIVE: Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown. METHODS: We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (S(I)) and (4) pancreatic function (“disposition index”, DI) by intravenous glucose tolerance test. RESULTS: At baseline, groups (risperidone: n = 28; olanzapine: n = 31) were overweight or obese by body mass index (risperidone: 28.4 ± 5.4, olanzapine: 30.6 ± 7.0 kg/m(2)). Both drugs induced weight gain (p < 0.004). Total adiposity was increased by olanzapine at 6 weeks (p = 0.0006) and by both treatments at 24 weeks (p < 0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p < 0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S(I), we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p < 0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p = 0.033), indicating inadequate pancreatic compensation for insulin resistance. CONCLUSIONS: This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications

Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function

© 2003 American Society for Clinical NutritionBackground: Flavonoids may be partly responsible for some health benefits, including antiinflammatory action and a decreased tendency for the blood to clot. An acute dose of flavanols and oligomeric procyanidins from cocoa powder inhibits platelet activation and function over 6 h in humans. Objective: This study sought to evaluate whether 28 d of supplementation with cocoa flavanols and related procyanidin oligomers would modulate human platelet reactivity and primary hemostasis and reduce oxidative markers in vivo. Design: Thirty-two healthy subjects were assigned to consume active (234 mg cocoa flavanols and procyanidins/d) or placebo (≤ 6 mg cocoa flavanols and procyanidins/d) tablets in a blinded parallel-designed study. Platelet function was determined by measuring platelet aggregation, ATP release, and expression of activation-dependent platelet antigens by using flow cytometry. Plasma was analyzed for oxidation markers and antioxidant status. Results: Plasma concentrations of epicatechin and catechin in the active group increased by 81% and 28%, respectively, during the intervention period. The active group had significantly lower P selectin expression and significantly lower ADP-induced aggregation and collagen-induced aggregation than did the placebo group. Plasma ascorbic acid concentrations were significantly higher in the active than in the placebo group (P &lt; 0.05), whereas plasma oxidation markers and antioxidant status did not change in either group. Conclusions: Cocoa flavanol and procyanidin supplementation for 28 d significantly increased plasma epicatechin and catechin concentrations and significantly decreased platelet function. These data support the results of acute studies that used higher doses of cocoa flavanols and procyanidins.Karen J. Murphy, Andriana K. Chronopoulos, Indu Singh, Maureen A. Francis, Helen Moriarty, Marilyn J. Pike, Alan H. Turner, Neil J. Mann, and Andrew J. Sinclai

Pharmacokinetics and bioavailability of the isoflavone biochanin A in rats

Biochanin A(BCA) is a dietary isoflavone present in legumes, most notably red clover, and in many herbal dietary supplements. BCA has been reported to have chemopreventive properties and is metabolized to the isoflavone genistein (GEN), BCA conjugates, and GEN conjugates. The metabolites may contribute to the chemopreventive effects of BCA. The absorption, metabolism, and disposition of BCA have not been determined in rats. Our objective was to evaluate the pharmacokinetics and metabolism of BCA in rats. Male Sprague-Dawley rats were administered BCA by intravenous injection (1 and 5 mg/kg), by intraperitoneal injection (5 and 50 mg/kg), and orally (5 and 50 mg/kg). Plasma and bile samples were enzymatically hydrolyzed in vitro to determine conjugate concentrations for BCA and GEN. Equilibrium dialysis was used to determine protein binding. The BCA and GEN concentrations in plasma, urine, and bile were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The pharmacokinetic parameters of BCA were analyzed by noncompartmental analysis. Significant levels of BCA conjugates and GEN conjugates were detected in plasma and bile. Both BCA and GEN were found to have a high clearance and a large apparent volume of distribution; the bioavailability of both was poor (<4%). Reentry peaks were evident after oral administration of both BCA and GEN, suggesting enterohepatic cycling. The free fraction of BCA in rat plasma was 1.5%. A2-compartment model that included both linear and nonlinear clearance terms and enterohepatic recirculation best described the plasma data. This represents the first evaluation of the dose-dependent pharmacokinetics and metabolism of BCA in rats