Hypokalemia in Patients with COVID-19.

BACKGROUND: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. METHODS: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. RESULTS: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3-3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36-4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08-3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228-1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170-1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222-1.047; P = 0.065) in our cohort of patients. CONCLUSIONS: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.

Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass.

AIMS/HYPOTHESIS: In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS: Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently-sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS: Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three- to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION: For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00433810.

Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement.

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min-1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min-1·kg-1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

Dissection of hepatic versus extra-hepatic insulin clearance: Ethnic differences in childhood.

AIMS: Adult African American (AA) women have one third of the hepatic insulin clearance of European American (EA) women. This lower hepatic (but not extra-hepatic) insulin clearance in AA individuals is associated with higher plasma insulin concentrations. This study aims to understand whether impairment of hepatic insulin clearance is seen in AA individuals since childhood, possibly suggesting that genetic/epigenetic factors, rather than lifestyle only, contribute to this. MATERIALS AND METHODS: A total of 203 children (105 male and 98 female (55 AA, 88 EA and 60 Hispanic American [HA]; ages, 7-13 years; mean BMI, 19 kg/m2 )) underwent the frequently applied intravenous glucose tolerance test (FSIGT) at the University of Alabama at Birmingham, General Clinical Research Center and Department of Nutrition Sciences. Glucose, insulin and C-peptide levels were measured and hepatic and extra-hepatic insulin clearances were calculated using mathematical modelling. RESULTS: Fractional hepatic insulin extraction (FEL ) was lower in AA than in EA children (mean (SD), 19% (20%) vs 33% (20%); P = 0.0007). Adjusting for age, Tanner stage and body fat, FEL was lower in AA than in EA children (P = 0.0012), and there was a slight sex-related difference (FEL, 24% (10%) vs 29% (10%) in boys vs girls; P = 0.04). Extra-hepatic insulin clearance did not differ with ethnicity (27 (12), 21 (12) and 24 (28) mL/kg/min for AA, HA and EA children, respectively; P > 0.05). CONCLUSIONS: At a young age, FEL is lower in AAs than in EAs, which does not rule out genetic/epigenetic factors. These differences are related to hyperinsulinaemia and, over time, could possibly contribute to metabolic disorders in AA individuals.

Performance of individually measured vs population-based C-peptide kinetics to assess ß-cell function in the presence and absence of acute insulin resistance.

AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate ß-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where ß-cell function is measured. METHODS: Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS: There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS: These data support the use of population-based measures of C-peptide kinetics to estimate ß-cell function during an OGTT.

Six and 12 Weeks of Caloric Restriction Increases ß Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes.

BACKGROUND: Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain. OBJECTIVE: We sought to quantify the effect of caloric restriction on ß cell function and glucose metabolism in people with type 2 diabetes. METHODS: Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m(2)): 40.6 ± 1.4; age: 58 ± 3 y; glycated hemoglobin: 6.9% ± 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure ß cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction. RESULTS: Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 ± 1.3, 5.9 ± 0.2, and 6.2 ± 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 ± 1.1, 16.2 ± 0.8, and 17.4 ± 1.1 µmol · kg(-1) · min(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in ß cell function measured by the disposition index (189 ± 51, 436 ± 68, and 449 ± 67 10(-14) dL · kg(-1) · min(-2) · pmol(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01). CONCLUSIONS: Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in ß cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054.

Cholecalciferol supplementation does not influence ß-cell function and insulin action in obese adolescents: a prospective double-blind randomized trial.

BACKGROUND: There is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes. OBJECTIVE: The objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D3) supplementation on insulin action (Si) and pancreatic ß-cell function in obese adolescents. METHODS: We performed a 12-wk double-blind, randomized comparison of the effect of vitamin D3 supplementation on Si and ß-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D3. Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate Si and ß-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group. RESULTS: Initial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 µg/L. There was no correlation between 25(OH)D concentrations and Si or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 µg/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in Si or DI following vitamin D3 supplementation in either of the treatment groups (all P > 0.10). CONCLUSIONS: The current study shows no effect from vitamin D3 supplementation, irrespective of its dose, on ß-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D3 supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.

Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp.

Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3-(3)H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 ± 0.64 vs. 8.73 ± 1.07 10(-4) dl·kg(-1)·min(-1) per µU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔI(clamp) = 15.60 ± 1.61 vs. ΔI(meal)= 83.37 ± 10.71 µU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test.

Proinsulin-to-C-Peptide Ratio as a Marker of ß-Cell Function in African American and European American Adults.

OBJECTIVE: The primary purpose of the current study was to test the hypothesis that the proinsulin-to-C-peptide (PI-to-CP) ratio, as an index of proinsulin secretion, would be higher and associated with indices of ß-cell function in African American adults relative to European American adults without type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants were 114 African American and European American adult men and women. A 2-h oral glucose tolerance test was conducted to measure glucose, insulin, C-peptide, and proinsulin and derive indices of ß-cell response to glucose. The Matsuda index was calculated as a measure of insulin sensitivity. The disposition index (DI), the product of insulin sensitivity and ß-cell response, was calculated for each phase of ß-cell responsivity. Pearson correlations were used to investigate the relationship of the PI-to-CP ratio with each phase of ß-cell response (basal, Φb; dynamic, Φd; static, Φs; total, Φtot), disposition indices (DId, DIs, DItot), and insulin sensitivity. Multiple linear regression analysis was used to evaluate independent contributions of race, BMI, and glucose tolerance status on PI-to-CP levels before and after adjustment for insulin sensitivity. RESULTS: African American participants had higher fasting and 2-h PI-to-CP ratios. The fasting PI-to-CP ratio was positively associated with Φb, and the fasting PI-to-CP ratio and 2-h PI-to-CP ratio were inversely associated with DId and insulin sensitivity only in African American participants. CONCLUSIONS: The PI-to-CP ratio could be useful in identifying African American individuals at highest risk for ß-cell dysfunction and ultimately type 2 diabetes.

Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin-resistant canine model.

OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin-resistant canine model. METHODS: A total of 12 dogs were fed a high-fat diet (HFD) for 6 weeks and then were given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. RESULTS: DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and ß-hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP-activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. CONCLUSIONS: For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin-resistant canine model.

Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.

BACKGROUND: Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. OBJECTIVES: To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. SETTING: Academic laboratory setting. METHODS: An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. RESULTS: Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. CONCLUSION: These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients.

Type 1 Tympanoplasty Outcomes between Cartilage and Temporal Fascia Grafts: A Long-Term Retrospective Study.

Background: To compare the functional and anatomical results of two different types of grafts in type 1 tympanoplasty (TPL I). Methods: A retrospective comparative bicentric study was conducted on patients treated with TPL I using temporal fascia or tragal cartilage. We evaluated the functional and anatomical results with intergroup and intragroup analyses. Variables predicting long-term success were also evaluated. Results: A total of 142 patients (98 fascia graft vs. 44 cartilage) were initially assessed, with a mean follow-up of 67.1 ± 3.2 months. No significant differences were observed between the two groups on the intergroup analysis of age, gender, ear side, or pre-operative hearing data (all p > 0.05). At the intragroup analysis of auditory outcomes, both groups demonstrated a significant improvement in post-operative air conduction, with greater gain for the fascia group at 6 months follow-up (p < 0.001 for both); however, at long-term follow-up, cartilage demonstrated better stability results (p < 0.001). When comparing the pre-and post-operative air-bone-gap (ABG), both groups showed a significant gain (p < 0.001); the fascia group showed that at 6 months, a greater ABG increase was found, but the difference was not statistically significant (4.9 ± 0.9 dB vs. 5.3 ± 1.2 dB; p = 0.04). On the contrary, the cartilage group at long-term follow-up at 5 years maintained greater outcomes (10 ± 1.6 dB vs. 6.4 ± 2 dB; p < 0.001). Lower age (F = 4.591; p = 0.036) and higher size of perforation (F = 4.820; p = 0.030) were predictors of long-term functional success. Conclusions: The graft material selection should consider several factors influencing the surgical outcome. At long-term follow-up, the use of a cartilage graft could result in more stable audiological outcomes, especially in younger patients or in case of wider perforations.

The Measurement of Insulin Clearance.

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of ß3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Novel aspects of the role of the liver in carbohydrate metabolism.

Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism ("glucose effectiveness"); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA.

Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes.

There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance is also lower in African American children 7-13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the ß-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lower insulin clearance can be a primary cause of type 2 diabetes in at-risk individuals.

Peripheral Mechanisms Mediating the Sustained Antidiabetic Action of FGF1 in the Brain.

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic ß-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of ß-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of ß-cell function and stimulation of HGU through increased hepatic glucokinase activity.

Enantioselective synthesis and olfactory evaluation of 13-alkyl-substituted alpha-ionones.

To study the influence of the steric bulk of the substituents at C(5) on the olfactory characteristics of alpha-ionone, the (S)-antipodes of compounds 8-10 were synthesized starting from (S)-alpha-cyclogeraniol (14a). The latter was available in useful preparative yield with 95% ee by enantioselective lipase-PS-mediated acetylation of the racemic mixture. Key step in the conversion of 14a to 8-10 was an S(N)2'-type reaction of an organocuprate on the allylic phosphate 20, which appears to be a general method for the introduction of an alkyl substituent at the cyclohexene C=C bond of ionones. Olfactory evaluation showed that, compared to the parent (S)-alpha-ionone (1), the odor strength and fragrance facets of the three analogues 8-10 are significantly influenced by the bulkiness of the substituent at C(13), giving further evidence that hydrophobic interactions of this group play a significant role in the chemoreception of ionones. In particular, the odor of the ethyl derivative 8 was found to be significantly stronger than that of the parent (S)-alpha-ionone (1).

Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women.

African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.

Oxytocin Improves ß-Cell Responsivity and Glucose Tolerance in Healthy Men.

In addition to its pivotal role in psychosocial behavior, the hypothalamic neuropeptide oxytocin contributes to metabolic control by suppressing eating behavior. Its involvement in glucose homeostasis is less clear, although pilot experiments suggest that oxytocin improves glucose homeostasis. We assessed the effect of intranasal oxytocin (24 IU) administered to 29 healthy, fasted male subjects on glucose homeostasis measured by means of an oral glucose tolerance test. Parameters of glucose metabolism were analyzed according to the oral minimal model. Oxytocin attenuated the peak excursion of plasma glucose and augmented the early increases in insulin and C-peptide concentrations in response to the glucose challenge, while slightly blunting insulin and C-peptide peaks. Oral minimal model analyses revealed that oxytocin compared with placebo induced a pronounced increase in ß-cell responsivity (PHItotal) that was largely due to an enhanced dynamic response (PHId), and a more than twofold improvement in glucose tolerance (disposition index). Adrenocorticotropic hormone (ACTH), cortisol, glucagon, and nonesterified fatty acid (NEFA) concentrations were not or were only marginally affected. These results indicate that oxytocin plays a significant role in the acute regulation of glucose metabolism in healthy humans and render the oxytocin system a potential target of antidiabetic treatment.