Metabolic modeling using statistical and spreadsheet software: Application to the glucose minimal model.

Kinetic non-linear metabolic models are used extensively in medical research and increasingly for clinical diagnostic purposes. An example of such a model is the Glucose Minimal Model by Bergman and colleagues [1]. This model is similar to pharmacokinetic/pharmacodynamic models in that like pharmacokinetic/pharmacodynamic models, it is based on a small number of fairly simple ordinary differential equations and it aims to determine how the changing concentration of one blood constituent influences the concentration of another constituent. Although such models may appear prima facie, to be relatively simple, they have gained a reputation of being difficult to fit to data, especially in a consistent and repeatable fashion. Consequently, researchers and clinicians have generally relied on dedicated software packages to do this type of modeling. This article describes the use of statistical and spreadsheet software for fitting the Glucose Minimal Model to data from an insulin modified intravenous glucose tolerance test (IM-IVGTT). A novel aspect of the modeling is that the differential equations that are normally used to describe insulin action and the disposition of plasma glucose are first solved and expressed in their explicit forms so as to facilitate the estimation of Glucose Minimal Model parameters using the nonlinear (nl) optimization procedure within statistical and spreadsheet software. The most important clinical parameter obtained from the Glucose Minimal Model is insulin sensitivity (SI). Using IM-IVGTT data from 42 horses in one experiment and 48 horses in a second experiment, we demonstrate that estimates of SI derived from the Glucose Minimal Model fitted to data using STATA and Excel, are highly concordant with SI estimates obtained using the industry standard software, MinMod Millennium. This work demonstrates that there is potential for statistical and spreadsheet software to be applied to a wide range of kinetic non-linear modeling problems.

Impact of type 2 diabetes on hospitalization and mortality in people with malignancy.

AIM: To compare the characteristics of and outcomes for people with malignancies with and without a co-diagnosis of diabetes. METHODS: Emergency department and hospital discharge data from a single centre for the period between 1 January 2015 and 31 December 2017 were used to identify people with a diagnosis of a malignancy and diabetes. Multivariate Cox regression models were used to estimate the effect of diabetes on all-cause mortality. A truncated negative binomial regression model was used to assess the impact of diabetes on length of hospital inpatient stay. Prentice-Williams-Peterson total time models were used to assess the effect of diabetes on number of emergency department re-presentations and inpatient re-admissions. RESULTS: Of 7004 people identified with malignancies, 1195 (17.1%) were also diagnosed with diabetes. A diagnosis of diabetes was associated with a greater number of inpatient re-admissions [adjusted hazard ratio 1.13 (95% CI 1.03, 1.24)], a greater number of emergency department re-presentations [adjusted hazard ratio 1.13 (95% CI 1.05, 1.22)] and longer length of stay [adjusted incidence rate ratio 1.14 (95% CI 1.04, 1.25)]. A co-diagnosis of diabetes was also associated with a 48% increased risk of all-cause mortality [adjusted hazard ratio 1.48 (95% CI 1.22-1.76)]. CONCLUSIONS: People with malignancies and diabetes had significantly more emergency department presentations, more inpatient admissions, longer length of hospital stay and higher rates of all-cause mortality compared to people with a malignancy without diabetes.

Automated vehicles and older drivers in Canada.

INTRODUCTION: As seniors represent a growing proportion of the driving population, research about how automated vehicles can help improve older driver safety and mobility is highly relevant. This paper examines the knowledge, attitudes and perceptions of older drivers towards limited self-driving vehicles (LSDVs), and how these variables can influence the likelihood that they will rely on this technology. METHOD: The study includes data from a previous national survey (N = 2662) about automated vehicle technology, with new analyses to test hypothetical models using structural equation modeling. Results of the first model were confirmed and built upon with a second more complex model that incorporated the construct "behavioral adaptation." Focus groups with older drivers were also conducted (N = 38) to help reveal nuances in older drivers' knowledge, attitudes, perceptions, and behaviors regarding this technology. RESULTS: Survey results demonstrated that feelings of safety and knowledge about LSDVs are positively related to perceived ease of use and adoption of the technology. The positive association between safety and perceived ease of use was further highlighted when comparing responses of older drivers to those of younger age groups, as older drivers were significantly less likely to agree that LSDVs were easy to use and were significantly less agreeable about feeling safe using them. Focus groups results confirmed that safety and knowledge of LSDVs are essential to the likelihood of adopting this technology, and revealed a high receptivity among older drivers to educational strategies and tools to increase their knowledge of LSDVs. Implications for educational strategies and safety benefits for older drivers are discussed. Practical applications: Results provide insight into strategies to encourage the early adoption of automated vehicles by older drivers and facilitate a safer transition towards automated vehicles that is lead by a cohort of safety-conscious drivers.

Canadian wildlife-vehicle collisions: An examination of knowledge and behavior for collision prevention.

OBJECTIVES: This study examines drivers' responses to wildlife on Canadian roads. The objective of this paper is to demonstrate that knowledge of what to do when encountering wildlife on the road does not always translate into the appropriate behavior to avoid a collision. METHODS: Data from the Traffic Injury Research Foundation's (TIRF) 2016 Road Safety Monitor (RSM) and data from TIRF's National Fatality Database from 2000 to 2014 were analyzed to test hypotheses based on the theory of planned behavior. Logistic regression and piecewise linear regression were used. RESULTS: Analyses of the data showed that the prevalence of fatal WVCs has remained relatively consistent, and that the majority of persons killed in WVCs died in crashes that involved large mammals. The majority of fatalities occurred in the summer (182 or 38.4%) and fall (163 or 34.4%). The RSM data revealed that 60.9% [50.5, 70.4] of respondents who previously hit an animal indicated that drivers should slow down and steer straight when confronted with wildlife, while 47.3% [37.1, 57.6] of respondents indicated this was the action they took when they hit wildlife. Comparatively, 59.5% [56.6, 62.4] of respondent who have not hit an animal indicated this was an appropriate response. Additionally, 33.2% [24, 44] of respondents who previously hit an animal indicated that drivers should swerve to avoid a collision with wildlife, while 37.5% [28.2, 47.8] of respondents indicated this was the action they took when they hit wildlife. CONCLUSIONS: Many drivers are unaware of what the safest method of WVC prevention is. Further, while a subgroup of drivers may have the knowledge and intention to slow down and steer straight even if the animal is directly in the path, i.e., the safest possible behavior, they are not necessarily adopting this behavior. Practical applications: Recommendations are formulated to address this discrepancy, as well as practical applications.

Marteilia refringens and Marteilia pararefringens sp. nov. are distinct parasites of bivalves and have different European distributions.

Marteilia refringens causes marteiliosis in oysters, mussels and other bivalve molluscs. This parasite previously comprised two species, M. refringens and Marteilia maurini, which were synonymized in 2007 and subsequently referred to as M. refringens 'O-type' and 'M-type'. O-type has caused mass mortalities of the flat oyster Ostrea edulis. We used high throughput sequencing and histology to intensively screen flat oysters and mussels (Mytilus edulis) from the UK, Sweden and Norway for infection by both types and to generate multi-gene datasets to clarify their genetic distinctiveness. Mussels from the UK, Norway and Sweden were more frequently polymerase chain reaction (PCR)-positive for M-type (75/849) than oysters (11/542). We did not detect O-type in any northern European samples, and no histology-confirmed Marteilia-infected oysters were found in the UK, Norway and Sweden, even where co-habiting mussels were infected by the M-type. The two genetic lineages within 'M. refringens' are robustly distinguishable at species level. We therefore formally define them as separate species: M. refringens (previously O-type) and Marteilia pararefringens sp. nov. (M-type). We designed and tested new Marteilia-specific PCR primers amplifying from the 3' end of the 18S rRNA gene through to the 5.8S gene, which specifically amplified the target region from both tissue and environmental samples.

Asymmetric changes in circulating insulin levels after an increase compared with a reduction in insulin pump basal rate in people with Type 1 diabetes.

AIMS: To investigate circulating insulin profiles after a clinically relevant insulin pump basal rate increase vs a reduction, and the associated glucose responses. METHODS: A cohort of 12 adults with Type 1 diabetes undertook this two-stage university hospital study using Accu-Chek pumps (Roche Diagnostics, Mannheim, Germany) and insulin aspart. An insulin basal rate change of 0.2 unit/h (increase in first stage, reduction in second stage) was implemented at ~09:30 h, after a single overnight basal rate (without bolus insulin), while fasting participants rested. Frequent venous samples for the assessment of plasma free insulin, glucose and cortisol were collected from 60 min before until 300 min after rate change. The primary outcome was time to steady-state insulin. RESULTS: The 0.2-unit/h rate change represented a mean ± sd alteration of 23 ± 6%. After the rate increase, the median (interquartile range) times to 80% and 90% steady-state insulin were 170 (45) min and 197 (87) min, respectively. By contrast, after rate reduction, 80% steady-state insulin was not achieved. After the rate increase, mean ± se insulin levels increased by 4.3 ± 3.1%, 12.0 ± 2.9% and 25.6 ± 2.6% at 60, 120 and 300 min, respectively (with no significant difference until 180 min). After the rate reduction, insulin decreased by 8.3 ± 3.0% at 300 min (with no significant difference until 300 min). After rate reduction, glucose levels paradoxically declined by 17.4 ± 3.7% after 300 min; cortisol levels also fell during observation (P = 0.0003). CONCLUSIONS: The time to circulating insulin change after a 0.2-unit/h basal rate change was substantial, and was greater after a reduction than after an increase. Counter-regulatory hormone circadian variation may affect glycaemia when implementing minor changes at low basal rates. Both direction of basal rate change, and time of day, warrant consideration when anticipating the clinical effects of basal rate changes.

An evaluation of Nova Scotia's alcohol ignition interlock program.

Alcohol ignition interlock programs for offenders aim to reduce recidivism among convicted drink drivers. This study presents an evaluation of Nova Scotia's interlock program implemented in 2008 in order to assess its effectiveness to reduce impaired driving and to help identify areas for improvement. Data used include conviction and crash records of individual participants; provincial monthly counts of alcohol-related charges, convictions and fatal and serious crashes; and interlock logged events. Methods used include descriptive statistics, survival analysis, time series and logistic regression analysis. With respect to specific deterrence (i.e., preventing recidivism) there was a 90% reduction in recidivism among voluntary participants since participation in the interlock program and a 79% reduction after these participants exited from the program. With respect to general deterrence (i.e., referring to a preventative effect on the entire population of drivers in Nova Scotia) there were temporary decreases in the numbers of alcohol-related charges (13.32%) and convictions (9.93%) and a small significant decrease in the number of fatal and serious injury alcohol-related crashes, following the implementation of the program. The evidence suggests the interlock program was better at preventing harm due to alcohol-impaired driving than the alternative of not using the interlock program. Recommendations were formulated supporting the continuation of the interlock program in Nova Scotia.

Prevalence and trends of drugged driving in Canada.

OBJECTIVES: This study evaluates prevalence and trends in drugged driving in Canada based on multiple indicators collected from the Road Safety Monitor (RSM) and Canada's National Fatality Database maintained by the Traffic Injury Research Foundation (TIRF). The objective of this paper is to identify the state of drug-positive driving in Canada, as well as to make comparisons with data from previous years to determine whether changes have occurred. METHODS: Available data from the RSM on self-reported drugged driving behaviours were collected and analyzed using multivariate techniques in various years spanning from 2002 to 2015. Data from TIRF's National Fatality Database from 2000 to 2012 were also analyzed to evaluate trends and prevalence of drugs in fatally injured drivers across Canada. Additionally, differences among drugged drivers with respect to gender and age were studied. RESULTS: Analyses of the RSM data and of the National Fatality Database showed that, as a whole, the prevalence of drugged driving has remained relatively stable over the past decade, with some changes noticed in specific years for some drug types. Specifically from the RSM, there was a 62.5% increase from the 1.6% of drivers reporting driving within two hours of using marijuana in 2013 to 2.6% in 2015. The analyses of the fatality data revealed a 16.9% increase in the percentage of fatally injured drivers testing positive for drugs between 2000 and 2012 (from 33.56% to 39.24%). Cocaine-positive fatally injured drivers increased from 3.6% in 2000 to 6.2% in 2012. Similarly, marijuana-positive fatally injured drivers increased from 12.8% in 2000 to 19.7% in 2012. Results showed varying characteristics with respect to gender and age among self-reported and fatally injured drugged drivers. CONCLUSIONS: Drugged driving behaviours remain prevalent among Canadian drivers and drugs continue to be found in over one-third of tested fatally injured drivers. Although self-reported behaviours have neither decreased nor increased overall in the past decade according to RSM data, with the exception of driving within two hours of using marijuana, data from fatally injured drivers reveal that small, but significant increases in some behaviours have occurred.

Multicenter Australian trial of islet transplantation: improving accessibility and outcomes.

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.

BACKGROUND: The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. OBJECTIVE: To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. SUBJECTS AND METHODS: FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. RESULTS: Si was lower in insulinoma patients before, compared with after surgery (3.37 +/- 0.62 vs. 6.24 +/- 1.09 SE [x10(-4)] min(-1)microU(-1) ml, P < 0.05). Sg was similar in patients pre- and post-surgery (3.0 +/- 0.67 vs. 2.4 +/- 0.6 [x10(-2)] min(-1), NS). CONCLUSIONS: Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.

Insulin secretion and insulin sensitivity are normal in non-diabetic subjects from maternal inheritance diabetes and deafness families.

BACKGROUND: The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus. AIM: To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation. METHODS: Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis. RESULTS: Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls. CONCLUSIONS: While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion.

Physiologic modeling of the intravenous glucose tolerance test in type 2 diabetes: a new approach to the insulin compartment.

The minimal model of Bergman et al has been used to yield estimates of insulin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by incorporating exogenous insulin protocols into the regular intravenous glucose tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiologic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeutic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/kg) and a "physiologic" insulin infusion throughout the IVGTT in a series of 8 patients, 5 of whom were insulin-requiring. Data from this approach were analyzed using the modelling program CONSAM to apply the Bergman model, either unmodified (BMM), or incorporating an additional delay element between the plasma and "remote" insulin compartments (MMD). Application of the MMD and extension of the IVGTT from 3 to 5 hours improved successful resolution of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subjects (1.86 +/- 0.60 v. 8.65 +/- 2.27 min(-1) x microU(-1) x mL x 10(4) P <.01). The results were validated in the type 2 diabetes group using a 2-stage euglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) x microU(-1) x mL x 10(4) P >.4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v. 1.55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabetic subjects was then analyzed using the MMD, but this approach did not enhance the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality whereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postulated that the physiologic basis for this delayed action may relate to transcapillary endothelial transfer of insulin, this process limiting the rate of onset of insulin action.

The Melbourne Pre-Diabetes Study: prediction of type 1 diabetes mellitus using antibody and metabolic testing.

OBJECTIVES: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus. PARTICIPANTS: 3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. MAIN OUTCOME MEASURES: Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in beta cell function over time; and development of clinical diabetes. RESULTS: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. CONCLUSIONS: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Impact of family history of diabetes on the assessment of beta-cell function.

Numerous factors impinge on beta-cell function, and include the genetic background and insulin sensitivity of the individual. The aim of the present study was to evaluate the impact of a family history of non-insulin-dependent diabetes mellitus (NIDDM) on beta-cell function and to determine whether the relationships between beta-cell function and insulin sensitivity and age are influenced by a family history of diabetes. Thirty-three healthy control subjects (CON), 20 normal glucose-tolerant first-degree relatives of known NIDDM patients (REL), and 12 nondiabetic identical twins with an identical twin with known NIDDM were studied. Insulin and C-peptide responses to an acute intravenous glucose (AIRg) and glucagon bolus (at euglycemia [AIR[G.GON]]) were measured, as well as each individual's insulin sensitivity. Fasting insulin and C-peptide levels were similar in all groups. AIRg was significantly reduced by 65% in the nondiabetic twins compared with the CON and REL groups, with the latter group being similar to CON, whereas for the AIR[G.GON], the insulin responses in the twin subjects were reduced only by 35% compared with CON. Following stepwise (default) multiple regression analysis, three independent variables (insulin sensitivity, 23%; family history of NIDDM, 20%; and fasting glucose, 7%) were identified, and these combined to fit a model for prediction of acute beta-cell responses to glucose that yielded an R2 (adjusted) value of 50%. Following analysis of covariance (ANCOVA), a positive family history of NIDDM and insulin sensitivity but not the age of the subject were confirmed as separate factors affecting AIRg. In conclusion, in subjects with normal or mild glucose intolerance, the individual's genetic background and insulin sensitivity are important determinants of insulin secretion.

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients.

We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 +/- 1.7 vs 29.6 +/- 1.6 years, BMI: 25.1 +/- 1.0 vs 25.1 +/- 0.9 kg/m2). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 +/- 0.2 [range: 3.2-7.0] vs 5.5 +/- 0.2 [3.7-7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 +/- 0.04 vs 0.34 +/- 0.04 10(-4) min(-1) per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 +/- 0.7 [3.9-17.0] vs 7.5 +/- 0.3 [5.7-9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These "hyperglycaemic" relatives had diminished first phase insulin secretion (O1) both before and during dex compared with the "normal" relatives and the control subjects (pre-dex O1: 12.6 +/- 3.6 vs 26.4 +/- 4.2 and 24.6 +/- 3.6 (p < 0.05), post-dex O1: 22.2 +/- 6.6 vs 48.0 +/- 7.2 and 46.2 +/- 6.6 respectively (p < 0.05) pmol x l(-1) x min(-1) per mg/dl). However, Si was similar in "hyperglycaemic" and "normal" relatives before dex (0.65 +/- 0.10 vs 0.54 +/- 0.10 10(-4) x min(-1) per pmol/l) and suppressed similarly during dex (0.30 +/- 0.07 vs 0.30 +/- 0.06 10(-4) x min(-1) per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state.

The effect of norepinephrine on insulin secretion and glucose effectiveness in non-insulin-dependent diabetes.

It has previously been shown that in normal subjects, physiological elevation of norepinephrine (NE) impairs insulin sensitivity (Si) but does not influence insulin secretion. The aim of this study was to determine the effect of short-term physiological elevation of NE on insulin secretion, Si, and glucose-mediated glucose disposal, or the glucose effectiveness index (Sg), in non-insulin-dependent diabetes mellitus (NIDDM). Two intravenous glucose tolerance tests (IVGTTs) were performed in eight well-controlled NIDDM patients, using a supplemental exogenous insulin infusion to achieve an approximation of normal endogenous insulin secretion. The IVGTTs were performed in random order after 30 minutes of either the saline (SAL) or NE (25 ng/kg/min) infusions, which were continued throughout the 3-hour IVGTT. Sg and Si were estimated by minimal model analysis of the IVGTT data as previously described. Plasma C-peptide was used to estimate insulin secretion rate using the ISEC program. NE infusion produced approximately a threefold increase in plasma NE, associated with (1) a significant reduction in glucose disposal ([KG] SAL v NE, 0.73 +/- 0.06 v 0.61 +/- 0.06 x 10(-2).min-1, P < .05), (2) no reduction in Si (2.33 +/- 0.8 v 2.62 +/- 0.9 x 10(-4).min-1/mU/L, NS), (3) a reduced mean second-phase insulin secretion rate (1.21 +/- 0.19 v 1.01 +/- 0.16 x 10(-3) pmol/kg/min per mmol/L glucose, P < .05), (4) a significant increase in Sg (0.89 +/- 0.08 v 1.63 +/- 0.2 x 10(-2).min-1, P < .05), and (5) a corresponding increase in glucose effectiveness at zero insulin ([GEZI] 0.55 +/- 0.13 v 1.30 +/- 0.33 x 10(-2).min-1, P < .05). These results show that in contrast to normal subjects, physiological elevation of NE in NIDDM does not result in a reduction in Si, but causes a reduction in glucose disposal related to inhibition of insulin secretion that is only partially compensated for by increased Sg.

A review of countermeasures to reduce radioiodine in milk of dairy animals.

The most effective countermeasure for radioiodine contamination of milk is to provide dairy animals with uncontaminated feed, with the added advantage that it will be effective for other radionuclides in the fallout. Another effective response is to process the milk into storable dairy products for an appropriate length of time to allow for physical decay. The use of additives given to ruminants to reduce radioiodine in milk is an alternative countermeasure which could be effective. Stable iodine administration is a practically feasible option which has the potential to reduce radioiodine levels in milk by at most a factor of three. Stable iodine supplementation should be at sufficiently high rates to be effective (and at least 1 g d-1 for dairy cows), particularly for ruminants already receiving high amounts of iodine in the diet. Currently available data are inadequate to recommend a suitable stable iodine administration rate for different species of ruminants. Other compounds, such as perchlorate and thiocyanate, also reduce the transfer to radioiodine to milk (and thyroid). Some of these compounds seem to be potentially equally as effective as stable iodine. However, currently there is inadequate information on their effectiveness and possible toxicity to both ruminants and humans for these compounds to be considered as suitable countermeasure additives.