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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.
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PMID:Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes. 1696 13

Various stimuli have been used in clinical practice to test islet function, including intravenous glucose, arginine--both at basal glucose levels and with the hyperglycaemic clamp, tolbutamide, glucagon and glucagon-like peptide 1. The subsequent first phase insulin response (also termed acute insulin response or AIR) to intravenous glucose or arginine has been quantified in a variety of ways, from the mean serum insulin measured at multiple times after glucose injection to the mean value above baseline of serum insulin at 2 to 10 min. The purpose of this study was to review the different protocols of AIR calculation and their pitfalls, and to assess the results of AIR in the islet transplantation field. By investigating the first phase of insulin secretion, AIR provides both a qualitative and a quantitative approach to insulin secretion. In islet transplantation, post-glucose AIR (AIRg) may predict graft survival while post-arginine AIR (AIRa) may be better correlated with engrafted beta cell mass, despite these facts need to be confirmed. AIRa also limits intravenous hyperglycaemia glucotoxicity. In conclusion, AIR could help to predict the need for a second or third islet injection in islet transplantation. These specific indications, however, need to be confirmed by future studies and completed by other approaches such as insulin sensitivity studies and in vivo morphological assessment of islet mass.
Diabetes Metab 2006 Sep
PMID:Acute insulin response (AIR): review of protocols and clinical interest in islet transplantation. 1697 56

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7-57 years. Outcomes included BMI, percent body fat, insulin sensitivity (S(i)), acute insulin response to glucose (AIR(g)), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIR(g) adjusted for S(i) in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with S(i). The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower S(i) and higher AIR(g) observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.
Diabetes 2006 Dec
PMID:Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with reduced insulin secretion in nondiabetic women. 1713 May 14

The diabetes epidemic and lack of adequate glycemic control in patients with diabetes emphasize the need for alternative diabetes treatment strategies. Although many new compounds have been developed, insulin remains the most potent agent for controlling glycemia. Inhaled insulin systems have been developed to alleviate the fear of insulin injections and to improve the convenience of insulin administration. The AIR Inhaled Insulin System being developed by Eli Lilly (Indianapolis, IN) and Alkermes (Cambridge, MA) uses AIR particle technology to deliver dry powder insulin to the deep lung. Pharmacokinetic and glucodynamic data in Phase 1 clinical trials have demonstrated that AIR Insulin is rapidly absorbed with prolonged insulin exposure and action compared to insulin lispro. AIR Insulin has also been shown to have dose equivalence and dose reproducibility across a range of doses, and it has been shown that three inhalations of the 2 U-equivalent dose can be interchanged with one 6 U-equivalent dose. A Phase 2 study demonstrated preference for AIR Insulin over subcutaneous injectable insulins, and a recent study reported that the system is easy to teach and use. Several Phase 3 studies are currently underway to further investigate the safety and efficacy and to evaluate the system's intention to meet provider and patient expectations.
Diabetes Technol Ther 2007 Jun
PMID:The AIR inhaled insulin system: system components and pharmacokinetic/glucodynamic data. 1756 3

Insulin therapy is underutilized in the treatment of diabetes mellitus for many reasons, including both patient and provider resistance. Targeting postprandial blood glucose control in patients with either type 1 or type 2 diabetes has been demonstrated to improve overall glycemic control, but the reluctance to use injectable insulin demonstrates the need for the development of alternative routes for insulin delivery. The development of inhaled insulin systems was designed to improve the ease of insulin use for patients and help alleviate fears they may have with injectable insulin. Human insulin inhalation powder (HIIP) (Eli Lilly, Indianapolis, IN/Alkermes, Cambridge, MA) has been demonstrated in Phase 2 studies to have similar effects on glycemic profiles compared to both insulin lispro and regular insulin. Hypoglycemia during HIIP was similar to that of regular insulin but was associated with greater hypoglycemic risk compared to insulin lispro. In addition, the AIR Inhaled Insulin system (Lilly/Alkermes), which delivers HIIP, has been demonstrated to be easy to use and requires minimal patient education, which may improve overall medication compliance. Phase 3 studies are ongoing to further evaluate safety and efficacy of HIIP.
Diabetes Technol Ther 2007 Jun
PMID:Review of phase 2 studies utilizing the AIR particle technology in the delivery of human insulin inhalation powder versus subcutaneous regular or lispro insulin in subjects with type 1 or type 2 diabetes. 1756 4

Over time, most patients with Type 2 diabetes require insulin-replacement therapy to attain and sustain the increasingly stringent glycemic goals. Initiation of subcutaneous insulin may be delayed due to patient or provider resistance. This delay may increase the risk of complications from long-term hyperglycemia. The development of inhaled insulin-delivery systems has been pursued to facilitate earlier initiation and optimization of insulin therapy to achieve better treatment outcomes. The AIR((R)) Inhaled Insulin System utilizes relatively large, low-density particles, allowing efficient drug delivery to the deep lung from a simple inhaler. In clinical studies it has provided similar postprandial glycemic control compared with subcutaneously injected, short-acting insulin, and was preferred by more patients. The purpose of this article is to describe the AIR Inhaled Insulin System, provide an overview of other insulin-delivery systems and discuss future strategies for the treatment of diabetes.
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PMID:AIR Inhaled Insulin System: a novel insulin-delivery system for patients with diabetes. 1785 Feb 3

Human type 2 diabetes mellitus (T2DM) is often characterized by obesity-associated insulin resistance (IR) and beta-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in beta-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n = 12) received a high-fat diet that increased visceral (52%, P < 0.001) and subcutaneous (130%, P < 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S(I)) (5.8 +/- 0.7 x 10(-4) to 4.1 +/- 0.5 x 10(-4) microU x ml(-1) x min(-1), P < 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30-15 mg/kg). The decrease in beta-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose >200 mg/dl during OGTT and 77-93% AIR(g) reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR(g) reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased beta-cell function (17-93%), and 40% lower S(I). We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.
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PMID:Novel canine models of obese prediabetes and mild type 2 diabetes. 1984 74

Several articles have investigated stochastic differential equations (SDEs) in PK/PD models, but few have quantitatively investigated the benefits to predictive performance of models based on real data. Estimation of first phase insulin secretion which reflects beta-cell function using models of the OGTT is a difficult problem in need of further investigation. The present work aimed at investigating the power of SDEs to predict the first phase insulin secretion (AIR (0-8)) in the IVGTT based on parameters obtained from the minimal model of the OGTT, published by Breda et al. (Diabetes 50(1):150-158, 2001). In total 174 subjects underwent both an OGTT and a tolbutamide modified IVGTT. Estimation of parameters in the oral minimal model (OMM) was performed using the FOCE-method in NONMEM VI on insulin and C-peptide measurements. The suggested SDE models were based on a continuous AR(1) process, i.e. the Ornstein-Uhlenbeck process, and the extended Kalman filter was implemented in order to estimate the parameters of the models. Inclusion of the Ornstein-Uhlenbeck (OU) process caused improved description of the variation in the data as measured by the autocorrelation function (ACF) of one-step prediction errors. A main result was that application of SDE models improved the correlation between the individual first phase indexes obtained from OGTT and AIR (0-8) (r = 0.36 to r = 0.49 and r = 0.32 to r = 0.47 with C-peptide and insulin measurements, respectively). In addition to the increased correlation also the properties of the indexes obtained using the SDE models more correctly assessed the properties of the first phase indexes obtained from the IVGTT. In general it is concluded that the presented SDE approach not only caused autocorrelation of errors to decrease but also improved estimation of clinical measures obtained from the glucose tolerance tests. Since, the estimation time of extended models was not heavily increased compared to basic models, the applied method is concluded to have high relevance not only in theory but also in practice.
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PMID:Predictive performance for population models using stochastic differential equations applied on data from an oral glucose tolerance test. 2001 4

OBJECTIVE Over half of newly diagnosed obese African Americans with diabetic ketoacidosis (DKA) discontinue insulin therapy and go through a period of near-normoglycemia remission. This subtype of diabetes is known as ketosis-prone type 2 diabetes (KPDM). RESEARCH DESIGN AND METHODS To investigate the role of lipotoxicity on beta-cell function, eight obese African Americans with KPDM, eight obese subjects with type 2 diabetes with severe hyperglycemia without ketosis (ketosis-resistant type 2 diabetes), and nine nondiabetic obese control subjects underwent intravenous infusion of 20% intralipid at 40 ml/h for 48 h. beta-Cell function was assessed by changes in insulin and C-peptide concentration during infusions and by changes in acute insulin response to arginine stimulation (AIR(arg)) before and after lipid infusion. RESULTS The mean time to discontinue insulin therapy was 11.0 +/- 8.0 weeks in KPDM and 9.6 +/- 2.2 weeks in ketosis-resistant type 2 diabetes (P = NS). At remission, KPDM and ketosis-resistant type 2 diabetes had similar glucose (94 +/- 14 vs. 109 +/- 20 mg/dl), A1C (5.7 +/- 0.4 vs. 6.3 +/- 1.1%), and baseline AIR(arg) response (34.8 +/- 30 vs. 64 +/- 69 microU/ml). P = NS despite a fourfold increase in free fatty acid (FFA) levels (0.4 +/- 0.3 to 1.8 +/- 1.1 mmol/l, P < 0.01) during the 48-h intralipid infusion; the response to AIR(arg) stimulation, as well as changes in insulin and C-peptide levels, were similar among obese patients with KPDM, patients with ketosis-resistant type 2 diabetes, and nondiabetic control subjects. CONCLUSIONS Near-normoglycemia remission in obese African American patients with KPDM and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. A high FFA level by intralipid infusion for 48 h was not associated with beta-cell decompensation (lipotoxicity) in KPDM patients.
Diabetes Care 2010 Mar
PMID:Lack of lipotoxicity effect on {beta}-cell dysfunction in ketosis-prone type 2 diabetes. 2002 38


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