Knowledge to action for solving complex problems: insights from a review of nine international cases.

INTRODUCTION: Solving complex problems such as preventing chronic diseases introduces unique challenges for the creation and application of knowledge, or knowledge to action (KTA). KTA approaches that apply principles of systems thinking are thought to hold promise, but practical strategies for their application are not well understood. In this paper we report the results of a scan of systems approaches to KTA with a goal to identify how to optimize their implementation and impact. METHODS: A 5-person advisory group purposefully selected 9 initiatives to achieve diversity on issues addressed and organizational forms. Information on each case was gathered from documents and through telephone interviews with primary contacts within each organization. Following verification of case descriptions, an inductive analysis was conducted within and across cases. RESULTS: The cases revealed 5 guidelines for moving from conceiving KTA systems to implementing them: (1) establish and nurture relationships, (2) co-produce and curate knowledge, (3) create feedback loops, (4) frame as systems interventions rather than projects, and (5) consider variations across time and place. CONCLUSION: Results from the environmental scan are a modest start to translating systems concepts for KTA into practice. Use of the strategies revealed in the scan may improve KTA for solving complex public health problems. The strategies themselves will benefit from the development of a science that aims to understand adaptation and ongoing learning from policy and practice interventions, strengthens enduring relationships, and fills system gaps in addition to evidence gaps. Systems approaches to KTA will also benefit from robust evaluations.

TITRE: Passer de la connaissance à l'action pour résoudre des problèmes complexes : aperçu de l'examen de neuf cas internationaux. INTRODUCTION: La résolution de problèmes complexes du type de la prévention des maladies chroniques présente des défis particuliers pour la création et le transfert de connaissances, soit le passage de la connaissance à l'action (PCA). Les approches axées sur le PCA respectant les principes de la pensée systémique sont jugées prometteuses, mais les stratégies pour les mettre en place ne sont pas bien comprises. Dans cet article, nous présentons les résultats d'une analyse de plusieurs approches systémiques axées sur le PCA dans le but de déterminer comment optimiser leur mise en oeuvre et leur efficacité. MÉTHODOLOGIE: Un groupe consultatif de cinq personnes a choisi neuf initiatives représentant une diversité d'enjeux et de formes organisationnelles. Pour chaque cas, l'information a été recueillie à partir de documents et par l'entremise d'entrevues téléphoniques avec des personnes-ressources de chaque organisation. Après la vérification des descriptions de cas, une analyse inductive a été effectuée à la fois pour chaque cas et entre les cas. RÉSULTATS: Ces cas ont révélé cinq lignes directrices permettant de passer de la conception de systèmes de PCA à leur mise en oeuvre : 1) établir et entretenir des relations, 2) coproduire et organiser les connaissances, 3) créer des boucles de rétroaction, 4) les encadrer comme des interventions systémiques plutôt que comme des projets et 5) envisager des variations dans le temps et selon les lieux. CONCLUSION: Les résultats de cette analyse contextuelle constituent un départ modeste pour transformer en résultats concrets les concepts systémiques de PCA. L'utilisation des stratégies mises au jour pourrait améliorer le PCA pour la résolution de problèmes complexes en matière de santé publique. Les stratégies elles-mêmes pourront bénéficier de l'évolution d'une science visant à comprendre l'adaptation et l'apprentissage constant des politiques et des interventions pratiques, ce qui renforcera les relations durables et comblera les lacunes des systèmes, et pas simplement celles des données probantes. Les approches systémiques de PCA tireront également des bénéfices d'évaluations rigoureuses.

Effect of chronic rosiglitazone, metformin and glyburide treatment on beta-cell mass, function and insulin sensitivity in mZDF rats.

Here we investigate the effect of rosiglitazone (RSG), metformin (MET) and glyburide (GLIB) on plasma glucose levels, beta-cell mass, function and insulin sensitivity in 10-week-old diabetic male Zucker diabetic fatty (mZDF) rats using quantitative morphometry and a mathematical model beta-cell mass, insulin and glucose kinetics (betaIG). At treatment start, 10-week-old diabetic mZDF rats were severely hyperglycaemic and had very low beta-cell function (insulin secretory capacity). RSG treatment significantly lowered plasma glucose levels in 67% of the mZDF rats. MET was effective at lowering plasma glucose levels in 33% of the mZDF rats, while GLIB was completely ineffective at lowering blood glucose levels in 10-week-old mZDF rats. RSG treatment prevented the fall in beta-cell mass after 6-8 weeks of treatment accompanied by a significant decrease in beta-cell death while MET treatment had no effect on beta-cell mass. RSG treatment increased insulin sensitivity 10-fold, increased beta-cell function fivefold and modestly increased beta-cell mass 1.4-fold. MET treatment increased insulin sensitivity fourfold, with no significant effect on beta-cell function or mass. Although RSG treatment was highly successful in lowering plasma glucose levels, the 33% of mZDF rats that did not respond to the treatment had significantly lower beta-cell function prior to treatment start compared with the responder group. Thus, the low level of beta-cell function at treatment start may explain why none of these agents were completely effective at lowering blood glucose levels in 10-week-old diabetic mZDF rats. Nevertheless, these data suggest that the preservation of beta-cell mass and improvement in beta-cell function play a role in the overall beneficial effect of RSG in 10-week-old diabetic mZDF rats.

Metabolic adaptations to chronic glucose infusion in rats.

AIMS/HYPOTHESIS: Several studies have employed the chronic glucose infusion protocol to quantify the metabolic adaptations associated with a prolonged glucose challenge. However, the limited number of indices and time points reported by these studies has generated an incomplete picture of this process. In this study we aimed to generate an integrative and dynamic picture of the physiological adaptations that occur during chronic glucose infusion. METHODS: Sprague-Dawley rats were infused with either 50% dextrose or saline (2 ml/h) for a period of between 0 and 6 days. Glucose, insulin and NEFA dynamics were determined from daily blood samples. Subsets of animals were killed daily for histological determination of beta cell mass, size and replication rates. The mathematical model of coupled beta cell mass, insulin and glucose (the betaIG model) was used to estimate insulin sensitivity, beta cell function and net neogenesis from this data. RESULTS: Glucose-infused rats displayed transient hyperglycaemia, persistent hyperinsulinaemia and unchanged NEFA levels. Insulin sensitivity decreased by approximately 80% during the first day of glucose infusion, but had returned to pre-infusion levels by Day 3. Beta cell function was four to six times higher than in control rats throughout the experiment. Beta cell mass doubled over the 6 days of glucose infusion due to three phases of adaptation: (i) neogenesis; (ii) hypertrophy and hyperplasia; and (iii) continued hyperplasia coupled to a second wave of neogenesis. CONCLUSIONS/INTERPRETATION: Contrary to the results reported for perfused pancreas and in vitro experiments, we found that chronic glucose infusion elevated beta cell function. The prediction of a second wave of beta cell neogenesis, coupled with our previous report of "focal areas" on Day 3, suggests the existence of delayed acinar-to-islet transdifferentiation.

The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes.

Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials.

Clearance of apoptotic beta-cells is reduced in neonatal autoimmune diabetes-prone rats.

The kinetics of beta-cell death in neonatal diabetes-prone (BBdp) and diabetes-resistant (BBdr) BioBreeding rats was investigated using both direct (histochemical) and indirect (mathematical modelling) techniques. In both BBdp and BBdr rats, the incidence of TUNEL positive beta-cells increased until 10 days of age before declining. The number of apoptotic beta-cells was significantly higher in BBdp as compared to BBdr neonates from birth until 20 days of age (P<0.05). Using a mathematical model applied to the time course of beta-cell mass and replication rate, a wave of net beta-cell loss was detected between 10 and 20 days of age in both strains. In contrast to the observed difference in the incidence of TUNEL positive beta-cells, with the model-based approach we found no difference in the rate of beta-cell apoptosis between BBdp and BBdr rats prior to weaning. As the number of apoptotic cells present in a tissue depends on the rate at which cells die and the rate at which the apoptotic cell debris is cleared, we compared in vitro phagocytosis of apoptotic thymocytes by peritoneal macrophages from 2-week-old BBdp and BBdr rats. Macrophages from BBdp neonates engulfed significantly less apoptotic cells as compared to BBdr neonates (P<0.0005). Taken together, these findings suggest that there is impaired clearance of apoptotic beta-cells in diabetes-prone BB rats during the neonatal period.

Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats.

The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are responsible for >50% of nutrient-stimulated insulin secretion. After being released into the circulation, GIP and GLP-1 are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV (DP IV). The use of DP IV inhibitors to enhance these insulinotropic hormonal axes has proven effective on an acute scale in both animals and humans; however, the long-term effects of these compounds have yet to be determined. Therefore, we carried out the following study: two groups of fa/fa Zucker rats (n = 6 each) were treated twice daily for 3 months with the DP IV inhibitor P32/98 (20 mg.kg(-1).day(-1), p.o.). Monthly oral glucose tolerance tests (OGTTs), performed after drug washout, revealed a progressive and sustained improvement in glucose tolerance in the treated animals. After 12 weeks of treatment, peak OGTT blood glucose values in the treated animals averaged 8.5 mmol/l less than in the controls (12.0 +/- 0.7 vs. 20.5 +/- 1.3 mmol/l, respectively). Concomitant insulin determinations showed an increased early-phase insulin response in the treated group (43% increase). Furthermore, in response to an 8.8 mmol/l glucose perfusion, pancreata from controls showed no increase in insulin secretion, whereas pancreata from treated animals exhibited a 3.2-fold rise in insulin secretion, indicating enhanced beta-cell glucose responsiveness. Also, both basal and insulin-stimulated glucose uptake were increased in soleus muscle strips from the treated group (by 20 and 50%, respectively), providing direct evidence for an improvement in peripheral insulin sensitivity. In summary, long-term DP IV inhibitor treatment was shown to cause sustained improvements in glucose tolerance, insulinemia, beta-cell glucose responsiveness, and peripheral insulin sensitivity, novel effects that provide further support for the use of DP IV inhibitors in the treatment of diabetes.

Effect of glucagon-like peptide 1 on non-insulin-mediated glucose uptake in the elderly patient with diabetes.

An important cause of elevated glucose levels in elderly patients with diabetes is an alteration in non-insulin-mediated glucose uptake (NIMGU). Glucagon-like peptide 1 (GLP-1) is an intestinal insulinotropic hormone. It has been proposed that this hormone also lowers glucose levels by enhancing NIMGU. This study was conducted to determine whether GLP-1 augments NIMGU in elderly patients with diabetes, a group in which NIMGU is known to be impaired. Studies were conducted on 10 elderly patients with type 2 diabetes (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) who underwent paired 240-min glucose clamp studies. In each study, octreotide was infused to suppress endogenous insulin release, and tritiated glucose methodology was used to measure glucose production and disposal rates. For the first 180 min, no glucose was infused. From 180 to 240 min, glucose was increased to 11 mmol/l using the glucose clamp protocol. In the GLP-1 study, GLP-1 was infused from 30 to 240 min. In a subsequent control study, insulin was infused using the glucose clamp protocol from 30 to 240 min to match the insulin levels that occurred during the GLP-1 infusion study. During hyperglycemia, GLP-1 enhanced glucose disposal (control study: 2.52 +/- 0.19 mg x kg(-1) x min(-1); GLP-1 study: 2.90 +/- 0.17 mg x kg(-1) x min(-1); P < 0.0001). Hepatic glucose output was not different between studies. We conclude that GLP-1 may partially reverse the defect in NIMGU that occurs in elderly patients with diabetes.

Beta-cell function and visceral fat in lactating women with a history of gestational diabetes.

Lactation has been recommended as beneficial for the maternal metabolic abnormalities associated with glucose intolerance and diabetes risk, although associations between breastfeeding (BF), glucose tolerance, and adipose tissue distribution are unknown. Therefore, a population of women with recent gestational diabetes (GDM) was evaluated with comparison of results for lactating versus nonlactating women. A total of 26 women participated (14 BF and 12 nonbreastfeeding [nonBF]) with a singleton vaginal delivery after 36 weeks gestation. At 3 months postpartum, each woman completed a 75-g oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), and computed tomography (CT) scanning for adipose distribution and mass. Insulin sensitivity was not significantly different between BF and nonBF groups (4.97 +/- 0.78 v 3.44 +/- 1.0 x 10(-4) min(-1)/(microU/mL) nor was glucose effectiveness (1.92 +/- 0.22 v 1.56 +/- 0.19 x 10(-2) min(-1)). However, the disposition index (DI) (insulin sensitivity [S(I)] x acute insulin response to glucose [AIRg]) was higher in the BF group (129.9 +/- 26.0 v 53.4 +/- 18.0 x 10(-4) min(-1); P =.03). Visceral fat (103 +/- 14 v 97 +/- 15 cm(2)) and subcutaneous fat (362 +/- 36 v 460 +/- 68 cm(2)) were similar between the groups. We conclude that 3 months of BF in a population with previous GDM was associated with improved pancreatic beta-cell function, but not with any difference in measures of adiposity.

Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death.

The evolution of diabetes in the male leptin receptor-deficient (fa/fa) Zucker diabetic fatty (ZDF) rat is associated with disruption of normal islet architecture, beta-cell degranulation, and increased beta-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased beta-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on beta-cell mass dynamics, male fa/fa (obese) and +/fa or +/+ (lean) rats age 6 weeks were fed either chow (control group [CN]) or chow mixed with rosiglitazone (RSG group) at a dosage of 10 micromol. kg(-1) body wt.day(-1). Rats were killed after 0, 2, 4, 6, or 10 weeks of treatment (at age 6, 8, 10, 12, or 16 weeks). Plasma glucose increased from 8.9 +/- 0.4 mmol/l at 0 weeks to 34.2 +/- 1.8 mmol/l (P = 0.0001) at 6 weeks of treatment in obese CN rats and fell from 8.0 +/- 0.3 to 6.3 +/- 0.4 mmol/l in obese RSG rats (P = 0.02). beta-cell mass fell by 51% from 2 to 6 weeks of treatment (ages 8-12 weeks) in obese CN rats (6.9 +/- 0.9 to 3.4 +/- 0.5 mg; P < 0.05), whereas beta-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), beta-cell mass in obese CN rats was only 56% of that of obese RSG rats (4.4 +/- 0.4 vs. 7.8 +/- 0.3 mg, respectively; P = 0.0001). The beta-cell replication rate fell from a baseline value of 0.95 +/- 0.12% in lean rats and 0.94 +/- 0.07% in obese rats (at 0 weeks) to approximately 0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, beta-cell replication was higher in obese RSG rats than in CN rats (0.59 +/- 0.14 vs. 0.28 +/- 0.05%, respectively; P < 0.02). Application of our mass balance model of beta-cell turnover indicated that net beta-cell death was fivefold higher in obese CN rats as compared with RSG rats after 6 weeks of treatment (age 12 weeks). The increase in beta-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r2 = 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net beta-cell death. beta-cell proliferation compensates for the increased beta-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond approximately 20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of beta-cell mass in obese ZDF rats by maintaining beta-cell proliferation and preventing increased net beta-cell death.

Dietary P(i) deprivation in rats affects liver cAMP, glycogen, key steps of gluconeogenesis and glucose production.

We previously reported [Xie, Li, Méchin and van de Werve (1999) Biochem. J. 343, 393-396] that dietary phosphate deprivation for 2 days up-regulated both the catalytic subunit and the putative glucose-6-phosphate translocase of the rat liver microsomal glucose-6-phosphatase system, suggesting that increased hepatic glucose production might be responsible for the frequent clinical association of hypophosphataemia and glucose intolerance. We now show that liver cAMP was increased in rats fed with a diet deficient in P(i) compared with rats fed with a control diet. Accordingly, in the P(i)-deficient group pyruvate kinase was inactivated, the concentration of phosphoenolpyruvate was increased and fructose 2, 6-bisphosphate concentration was decreased. Phosphoenolpyruvate carboxykinase activity was marginally increased and glucokinase activity was unchanged by P(i) deprivation. The liver glycogen concentration decreased in the P(i)-deficient group. In the fed state, plasma glucose concentration was increased and plasma P(i) and insulin concentrations were substantially decreased in the P(i)-deficient group. All of these changes, except decreased plasma P(i), were cancelled in the overnight fasted P(i)-deficient group. In the fasted P(i)-deficient group, immediately after a glucose bolus, the plasma glucose level was elevated and the inhibition of endogenous glucose production was decreased. However, this mild glucose intolerance was not sufficient to affect the rate of fall of the glucose level after the glucose bolus. Taken together, these changes are compatible with a stimulation of liver gluconeogenesis and glycogenolysis by the P(i)-deficient diet and further indicate that the liver might contribute to impaired glucose homeostasis in P(i)-deficient states.

A model of beta-cell mass, insulin, and glucose kinetics: pathways to diabetes.

Diabetes is a disease of the glucose regulatory system that is associated with increased morbidity and early mortality. The primary variables of this system are beta-cell mass, plasma insulin concentrations, and plasma glucose concentrations. Existing mathematical models of glucose regulation incorporate only glucose and/or insulin dynamics. Here we develop a novel model of beta -cell mass, insulin, and glucose dynamics, which consists of a system of three nonlinear ordinary differential equations, where glucose and insulin dynamics are fast relative to beta-cell mass dynamics. For normal parameter values, the model has two stable fixed points (representing physiological and pathological steady states), separated on a slow manifold by a saddle point. Mild hyperglycemia leads to the growth of the beta -cell mass (negative feedback) while extreme hyperglycemia leads to the reduction of the beta-cell mass (positive feedback). The model predicts that there are three pathways in prolonged hyperglycemia: (1) the physiological fixed point can be shifted to a hyperglycemic level (regulated hyperglycemia), (2) the physiological and saddle points can be eliminated (bifurcation), and (3) progressive defects in glucose and/or insulin dynamics can drive glucose levels up at a rate faster than the adaptation of the beta -cell mass which can drive glucose levels down (dynamical hyperglycemia).

Minimal-model estimates of insulin sensitivity are insensitive to errors in glucose effectiveness.

The minimal-model method allows for estimation of insulin sensitivity (S(I) = P(3)/P(2)) and glucose effectiveness (S(G) = P(1)) from the time course of glucose and insulin after a glucose bolus. We previously demonstrated that the minimal-model results in overestimates of S(G) in subjects with normal insulin secretory function. To determine whether overestimation of S(G) has an impact on estimation of S(I), we examined model estimation of S(I) when S(G) was constrained to levels below that found by the regular minimal-model fit. Fifty-six glucose tolerance tests from lean and obese women, with and without polycystic ovary syndrome, were used. S(I) ranged from 0.2-22.6 x 10(-4) min(-1)/(microU/mL), and S(G) ranged from 0.8-3.8 x 10(-2) min(-1) for the standard minimal-model fits. Constraining S(G) to as low as 40% of the unconstrained value resulted in a 4-fold increase in P2 and P3, but only a 3% reduction in S(I). We conclude that estimation of the insulin sensitivity index is independent of errors in minimal-model-derived estimates of glucose effectiveness.

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

Prior streptozotocin treatment does not inhibit pancreas regeneration after 90% pancreatectomy in rats.

The effects of residual beta-cell mass and glycemia on regeneration of endocrine pancreas after 90% pancreatectomy were investigated. Streptozotocin or buffer alone was injected into 4-wk-old male Lewis rats (day 0). On day 7, varying numbers of syngeneic islets were transplanted under the kidney capsule to achieve varying degrees of glucose normalization. On day 14, a 90% pancreatectomy or sham pancreatectomy was performed. On day 19, rats were killed and the pancreas was fixed for quantitative morphometric determination of beta-cell mass. Focal areas of regenerating pancreas were observed in all animals that underwent partial pancreatectomy. The percentage of remnant pancreas classified as foci was unaffected by streptozotocin treatment or by plasma glucose. Moderate to severe hyperglycemia did not promote regeneration of the pancreatic beta-cell mass; rather the total endocrine cell mass was inversely related to the plasma glucose level (r = -0.5, P < 0.01). These data suggest that the precursor population for both endocrine and exocrine tissue is not susceptible to damage by streptozotocin and that local effects of residual beta-cell mass are not important to regeneration after a 90% pancreatectomy.

Glucose effectiveness is the major determinant of intravenous glucose tolerance in the rat.

To determine the importance of insulin for glucose disposal during an intravenous glucose tolerance test in rats, experiments were performed in four cohorts of conscious unrestrained rats fasted overnight. In cohorts 1-3, a bolus of tracer ([3-3H]glucose, 50 microCi) was given alone, with glucose (0.3 g/kg) to induce an endogenous insulin response (approximately 1,100 pmol/l), or with exogenous insulin to give physiological (1,700 pmol/l) or supraphysiological (12,000 pmol/l) plasma levels. Raising plasma insulin within the physiological range had no effect (P > 0.05), but supraphysiological levels induced hypoglycemia (7.3 +/- 0.2 to 3.6 +/- 0.2 mmol/l) and increased [3H]glucose disappearance rate (P < 0.001). In cohort 4, a primed, continuous tracer infusion was started 120 min before saline or glucose bolus injection. [3H]glucose levels fell 15-20%, and the disappearance rate rose 36% (P < 0.05) after glucose injection. These results indicate that in fasted rats a tracer bolus injection protocol is not sufficiently sensitive to measure the physiological effect of insulin released in response to a bolus of glucose because this effect of insulin is small. Glucose itself is the predominant mediator of glucose disposal after a bolus of glucose in the fasted rat.

Assessing insulin sensitivity in the cat: evaluation of the hyperinsulinemic euglycemic clamp and the minimal model analysis.

Current methods of assessing glucose tolerance in the cat are inadequate for quantifying insulin sensitivity. The hyperinsulinemic euglycemic clamp (EGC) and the minimal model analysis (MMA) of the frequently sampled intravenous glucose tolerance test (FSIGT) have been used in other species to assess the effects of insulin on glucose homeostasis. Each of these procedures was performed on healthy cats, two weeks apart, to generate indices of insulin sensitivity - M/I (amount of glucose metabolised per unit of plasma insulin concentration) from the EGC and S(I) (insulin sensitivity) from the MMA. Close and significant correlation between M/I and S(I) in individual cats was found (r=0.91, P=0.032). Use of these research methods may further our understanding of feline diabetes mellitus and other endocrinopathies.

Alterations in non-insulin-mediated glucose uptake in the elderly patient with diabetes.

It is increasingly recognized that alterations in non-insulin-mediated glucose uptake (NIMGU) play an important pathogenic role in disorders of carbohydrate metabolism. This study was conducted to determine whether NIMGU is impaired in elderly patients with type 2 diabetes. Healthy elderly control subjects (n = 19, age 76 +/- 1 years, BMI 26.8 +/- 1.1 kg/m2) and elderly patients with type 2 diabetes (n = 19, age 76 +/- 2 years, BMI 27.5 +/- 0.9 kg/m2) underwent a 240-min glucose clamp study. Octreotide was infused to suppress endogenous insulin release, and tritiated glucose methodology was used to measure glucose uptake and disposal rates. For the first 180 min, glucose was kept at fasting levels. From 180 to 240 min, glucose was increased to 11 mmol/l. At fasting glucose levels, glucose uptake was similar in both groups. However, glucose clearance was reduced in patients with diabetes (control 1.68 +/- 0.05 ml x kg(-1) x min(-1); diabetes 1.34 +/- 0.07 ml x kg(-1) x min(-1), P < 0.0001). During hyperglycemia, glucose uptake was reduced in patients with diabetes (control 3.16 +/- 0.09 mg x kg(-1) x min(-1); diabetes 2.57 +/- 0.11 mg x kg(-1) x min(-1), P < 0.0001). Peripheral glucose effectiveness (SG) was less in patients with diabetes (control 1.28 +/- 0.04 ml x kg(-1) x min(-1); diabetes 0.94 +/- 0.08 ml x kg(-1) x min(-1), P < 0.0001). Hepatic glucose output and hepatic SG were not different between groups. We conclude that the effect of glucose on glucose uptake is impaired in elderly patients with type 2 diabetes, a finding that may have therapeutic implications for this patient population.

Relation among left ventricular mass, insulin resistance, and blood pressure in nonobese subjects.

Because left ventricular (LV) mass (LVM) is a powerful predictor of future cardiovascular events, it is important to identify hemodynamic and nonhemodynamic factors that increase LVM. We studied the separate contribution to LVM of daily arterial blood pressure (BP) and insulin resistance in a consecutive series of 29 (mean+/-SD age, 43+/-13 yr) nonobese (body mass index, 24+/-1.8 kg/m2), nondiabetic, glucose-tolerant subjects with untreated borderline or mild hypertension. The insulin sensitivity index (SI) was quantitatively determined from the frequently sampled iv glucose tolerance test. BP was characterized by ambulatory 24-h BP monitoring, and LVM index (LVMI) was determined by two-dimensional directed M-mode echocardiography. LVMI was directly related to 24-h mean BP (r=0.47; P=0.01). LMVI was also significantly related to Si (r=-0.43; P=0.02). In this nonobese group, neither LVMI nor Si was related to body mass index or age. After adjustment for the influence of BP on LVMI, a significant relation remained between LVMI and Si (P < 0.05). We conclude that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP and may be an important modulator of LV growth. In addition to a reduction of arterial BP, optimal prevention of LV hypertrophy in hypertensives may require improved insulin sensitivity.