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PubMed2004

Cardiac dysfunction in the euglycemic diabetic-prone BB Wor rat.

The purpose of this study was to examine cardiac function in the diabetic-prone BB Wor rat. The study involved 2 groups: diabetic resistant control littermates of BB rats and diabetic-prone BB rats that had yet to demonstrate overt signs of diabetes. Hearts from these animals were isolated and cardiac function examined in response to incremental increases in left atrial filling pressure. Hearts were also perfused at an increased aortic afterload resistance with buffer consisting of glucose alone or glucose in the presence of palmitate. Hearts from diabetic-prone rats exhibited depressed contractility and ventricular relaxation at high filling pressures. Ventricular function, expressed as cardiac output, was also depressed in diabetic-prone rats perfused at increased afterload resistance, but only in the presence of palmitate. Our results indicate that hearts from diabetic-prone BB Wor rats demonstrate abnormalities in contractile performance and thus may be a useful model for the study of cardiac function in the prediabetic state.

Animals↗

PubMed2004

Importance of NPY Y1 receptor-mediated pathways: assessment using NPY Y1 receptor knockouts.

The peptidic neurotransmitter neuropeptide Y (NPY) has been functionally implicated in feeding behavior, cardiovascular regulation, control of neuroendocrine axes, affective disorders, seizures, and memory retention. At least five different receptors mediate NPY actions. In particular, the Y1 receptor appears to be involved in a variety of NPY-induced pathways. This review summarizes the main findings resulting from the use of mice lacking NPY Y1 receptor expression. Interestingly, the overall phenotype of Y1 knockouts mimics metabolic syndrome, which is characterized by obesity, a prediabetic state, and a susceptibility to develop hypertension.

Animals↗

PubMed1996

Differential beta-cell response to glucose, glucagon, and arginine during progression to type I (insulin-dependent) diabetes mellitus.

Acute insulin responses to glucose (AIRG), glucagon (AIRGln), and arginine (AIRArg) were evaluated prospectively in nine subjects positive for islet-cell antibodies (ICAs) who later progressed to type I diabetes or impaired glucose tolerance (IGT) (progressors), 64 ICA-positive subjects at risk who did not develop type I diabetes, 365 ICA-negative relatives of diabetic patients who also remained free of the disease, and 89 control subjects. Seven progressors already had a low AIRG at entry into the study, and the other two became low responders 3 to 9 months before diabetes or IGT, with a progressive decline of AIRG over serial intravenous (IV) glucose tolerance tests. At entry into the study, the group of progressors displayed lower AIRG, AIRGln, and AIRArg than the other three groups (P<.001). However, AIRArg was less altered than AIRG. During the course of the prediabetic phase, there was a progressive decline in AIRG and AIRGln analyzed as a function either of time (P<.006) or of basal glycemia (P<.05), ie, two different ways of estimating worsening of the disease process. Conversely, there was no significant decrease in AIRArg with time or with increasing basal glycemia, so that AIRArg was not totally blunted in these prediabetic subjects even a few months before the onset of diabetes. The persistence of a substantial response to arginine, ie, higher than the fifth control percentile, even at a late stage, was confirmed in five of nine diabetic patients tested either at onset of the disease or during non-insulin-receiving remission. Whereas AIRG deteriorates during prediabetes, AIRArg appears to be less altered with time and increased basal glycemia, remaining substantial even at the onset of the disease. This reinforces the supposition that the prediabetic state may be associated with a glucose-specific beta-cell functional abnormality in addition to a decreasing beta-cell mass.

Adolescent↗

PubMed2002

[From obesity to diabetes].

The major risk factor for the development of insulin resistance and type 2 diabetes is obesity. A key role is the new understanding of adipocytes as an endocrine system. Adipocytes secrete numerous substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. There is also a role of free fatty acids by blocking directly intracellular metabolism of glucose and by their lipotoxicity. The pre-receptor metabolism of cortisol may be enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. The new class of thiazolidinediones (glitazones), binding to the peroxisome proliferator activated receptor (PPAR-gamma) lowers the levels of resistin and increases adiponectin, resulting in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance should be an attempt to reduce body weight and to increase physical activity. These are successful means to avoid the development of type 2 diabetes from prediabetic states, as shown recently in 3 independent intervention trials.

Adipose Tissue↗

PubMed2003

Insulin resistance--the new goal!

Diabetes mellitus is a well-recognized risk-factor for coronary artery disease (CAD). Epidemiological studies have shown that the risk of CAD increases two to sixfold in patients with type 2 diabetes compared with those without the disease. Furthermore the prevalence of diabetes in the UK has increased by 30% since 1991 and the world population of people with diabetes in 2010 is expected to be twice that of 1990. In addition whilst the mortality from CAD in patients without diabetes has declined over the past 20 years the mortality in men with type 2 diabetes has not changed and in women may have increased. UKPDS and other studies have shown a significant improvement in the onset and course of microvascular complications with good diabetic control. However the same is not true for macrovascular complications for which there is no good evidence of improvement with better diabetic control. This apparent lack of benefit from improved care of diabetic patients has led to many different approaches. These include attempts to achieve even better glycaemic control, greater emphasis on other risk factors particularly hypertension and interestingly attention to the prediabetic state characterized by insulin resistance (IR). The latter is associated with a number of abnormalities which could play a causative role in the development of cardiovascular disease. This article will review the concept of IR and the possible interventions available to tackle it.

Cardiovascular Diseases↗

PubMed2003

Risk stratification and management of sudden cardiac death: a new paradigm.

Risk Stratification and Management of SCD. Management of SCD is undergoing radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiologic processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large.

Coronary Artery Disease↗

PubMed1987

Cell-mediated immune reactions against islets of Langerhans in diabetes-prone BB rats.

The intact pancreatic islet can be destroyed by antibody-dependent cell-mediated cytotoxicity (ADCC). T cell-mediated cytotoxicity (CMC) might additionally be important in the pathogenesis of IDDM. However, in vitro alterations of islets due to CMC have so far not been demonstrated. For the evaluation of the cytotoxic attack caused by ADCC and CMC against the islets in the development of IDDM we used a BB rat line with a high incidence of the disease (dp BB/OK). Cytotoxicity tests were carried out on autologous and on nonsyngeneic islets with mononuclear spleen cells and serum from non-diabetic BB rats of different ages. The cytotoxic action of the mononuclear cells was quantified by the specific 51Cr-release from the islets after pretreatment with serum. It was found that an anti-islet cytotoxicity appears with a peak incidence between 40 and 60 days of age. The frequency of cytotoxicity in vitro was related to the incidence of diabetes as normally observed in this rat line. Furthermore, it was shown that both autologous, allogeneic and xenogeneic islets can be destroyed by mononuclear spleen cells and serum of dp BB/OK rats.--The frequency and the strength of anti-islet cytotoxicity in vitro were higher in these dp BB/OK animals than in a control group of non-diabetes prone BB/PhiK rats. There was an association between cytotoxic 51Cr-release in the positive assays and a reduction in the hormone content of pancreatic islets.--This report provides evidence of cell-mediated immune damage of islets during the prediabetic state of BB rats suggesting that both CMC and ADCC are involved in islet cell killing.

Animals↗

PubMed1989

3H-thymidine incorporation into islets obtained from prediabetic BB rats.

DNA synthesis, measured as 3H-thymidine incorporation, was estimated in islets obtained from BB rats before the onset of diabetes and compared with the replication rate of islets obtained from age-matched BB rats having never developed hyperglycaemia. Using a biopsy procedure, splenic pancreas was removed from both 65 and from 80 day old diabetes prone BB rats. After isolation by a modified collagenase method pancreatic islets were incubated with labeled thymidine. The animals submitted to biopsy were followed up until they reached an age of 200 days. The diabetes incidence of the BB rats biopsied at day 65 and at day 80 was comparable (35% and 31%). In both groups approximately 140 mg of splenic pancreas were necessary to isolate 70-90 islets, regardless whether the animals become diabetic or not. Using a retrospective experimental design, the thymidine incorporation into islets obtained from prediabetic (rats which developed hyperglycaemia) and from normoglycaemic BB rats were comparatively analysed. The DNA synthesis of pancreatic islets obtained from 65 day old prediabetic BB rats is not different from that measured in islets from normoglycaemic BB rats. A similar replicatory behaviour was also observed using islets from prediabetic and normoglycaemic 80 day old BB rats. From our results we seek to conclude that a prediabetic state is not related to a diminished replicatory activity of pancreatic islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Prevalence of diabetes-specific autoantibodies in patients at risk for adult onset diabetes mellitus.

To evaluate the potential of autoimmune markers in identifying patients with slowly progressive IDDM in the prediabetic state, we screened a population of 151 patients aged 37-70 years with impaired glucose tolerance (IGT) for the presence of islet cell antibodies (ICA), insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GADA), and antibodies to tyrosine phosphatase IA-2 (IA-2A). Autoantibodies were found in 5 (3.3%) patients with IGT suggesting the presence of an autoimmune-mediated beta cell destruction. All of them were positive for high level ICA (> 20 JDF-U) and 1 ICA positive subject had additional GADA (100 GADA-U). In contrast, none of the subjects had IA-2A or IAA. We here demonstrate a low prevalence of autoimmune diabetes among middle-aged subjects with IGT. ICA and GADA but not IA-2A or IAA may represent autoimmune markers for slowly progressive IDDM before the manifestation of the disease.

Adult↗

PubMed2004

Abnormal regulation of maternal cerebral blood flow under conditions of gestational diabetes mellitus.

AIM: Gestational diabetes mellitus is a prediabetic state leading to endothelial dysfunction and altered organ perfusion. Under normal conditions cerebral blood flow is closely coupled to cortical activity, to which it rapidly adjusts. On the basis of this so-called neurovascular coupling we evaluated the influence of a gestational diabetic state on endothelium-dependent vasoregulative properties of this mechanism. METHOD: A functional transcranial Doppler test performed during visual stimulation was used to measure vascular reactivity. Peak systolic and end-diastolic flow velocity response from 20 non-pregnant (age 27 +/- 6 y), 31 healthy pregnant women (31 +/- 6 y; 31 +/- 4 gestational week) and 30 women with gestational diabetes (32 +/- 5 y; 34 +/- 4) were separately evaluated according to a control system approach. All women did not show any vascular risk factors prior to pregnancy. RESULTS: Comparison of resting blood flow velocity and the control system parameters of gain, attenuation, rate time and natural frequency, showed a consistent and significant difference in the parameter "attenuation" for the peak systolic data (0.55 +/- 0.18 vs. 0.44 +/- 0.1 and 0.45 +/- 0.11, p < 0.01) as well as end-diastolic (0.61 +/- 0.23 vs. 0.49 +/- 0.2 and 0.5 +/- 0.14, p < 0.05) figures (mean +/- SD of value from women with gestational diabetes vs. non-pregnant and healthy pregnant women, significance level). No differences were found between non-pregnant and normal pregnant women for the neurovascular coupling mechanism. CONCLUSIONS: Gestational diabetes mellitus results in endothelial dysfunction which can be measured in a non-invasive, painless and easy manner by a transcranial Doppler test.

Adult↗

PubMed1998

Evidence from transgenic mice that interferon-beta may be involved in the onset of diabetes mellitus.

A number of cytokines have been shown to alter the function of pancreatic beta-cells and thus might be involved in the development of type 1 diabetes. Interferon-beta (IFN-beta) expression is induced in epithelial cells by several viruses, and it has been detected in islets of type 1 diabetic patients. Here we show that treatment of isolated mouse islets with this cytokine was able to alter insulin secretion in vitro. To study whether IFN-beta alters beta-cell function in vivo and leads to diabetes, we have developed transgenic mice (C57BL6/SJL) expressing IFN-beta in beta-cells. These mice showed functional alterations in islets and impaired glucose-stimulated insulin secretion. Transgenic animals presented mild hyperglycemia, hypoinsulinemia, hypertriglyceridemia, and altered glucose tolerance test, all features of a prediabetic state. However, they developed overt diabetes, with lymphocytic infiltration of the islets, when treated with low doses of streptozotocin, which did not induce diabetes in control mice. In addition, about 9% of the transgenic mice obtained from the N3 back-cross to outbred albino CD-1 mice spontaneously developed severe hyperglycemia and hypoinsulinemia and showed mononuclear infiltration of the islets. These results suggest that IFN-beta may be involved in the onset of type 1 diabetes when combined with either an additional factor or a susceptible genetic background.

Animals↗

PubMed2006

The mean platelet volume in subjects with impaired fasting glucose.

Mean platelet volume (MPV), a determinant of platelet function, is a newly emerging risk factor for atherothrombosis. Impaired fasting glucose (IFG) is probably a frequent glycemic disorder in the general population and is considered as a prediabetic state. The present study was designed to evaluate MPV in subjects with IFG compared with diabetic patients and normoglycemic control subjects. We selected 50 patients with type 2 diabetes mellitus, 50 subjects with IFG, and 50 normoglycemic healthy subjects matched for age, gender, and body mass index. MPV was very significantly higher in diabetic and IFG groups than in control group (p < 0.00, p < 0.05, respectively); it was also higher in diabetic group than in IFG group (p < 0.05). Platelet counts were not different among the study groups (p > 0.05). Platelet mass was significantly higher in diabetic and IFG groups than in normotensives (p < 0.00, p < 0.05, respectively); and it was also higher in diabetic group than in IFG group (p < 0.05). MPV and platelet mass were positively correlated with fasting glucose and HbA1c in diabetic and IFG groups (p < 0.05). In conclusion, our data suggests one possible mechanism by which subjects with IFG may be at increased cardiovascular risk.

Blood Glucose↗

PubMed2000

Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation.

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The nonobese patient with diabetes (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific. We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting.

Animals↗

PubMed2006

Effect of genistein with carnitine administration on lipid parameters and obesity in C57Bl/6J mice fed a high-fat diet.

Soy products are mainly composed of proteins, phytochemicals such as isoflavones, soy lipids, and carbohydrates. It is unclear whether an individual component alone or a combined effect of multiple bioactive compounds contributes to the beneficial properties of soy. We investigated the effect of dietary genistein (the principal soy isoflavone) alone and combined with L-carnitine to evaluate possible synergistic effects on the intentionally induced prediabetic state characterized by insulin resistance and obesity in C57Bl/6J mice fed a high-fat diet (HD). In the HD-alone group, abdominal and back fat relative to total body weight were significantly higher compared with other groups including those fed normal diet (ND). Among the HD groups, final weight gains of the HD plus genistein (HD+G) and HD plus genistein plus L-carnitine (HD+G+C) groups were lower compared with that of the control (HD-alone). Especially in liver, the results showed that genistein with carnitine transcriptionally up-regulated expressions of acyl-coenzyme A synthetase (ACS) and carnitine palmitoyltransferase-I (CPT-I) by approximately 50% and 40%, respectively, compared with genistein alone. However, the up-regulation of CPT-I did not directly reflect the enzyme activity of CPT-I. On the other hand, the effects of genistein and genistein with carnitine on the expressions of ACS and CPT-I in muscle were not significant. Our study suggests that genistein with carnitine exerts anti-obesity effects, probably by modulating peroxisome proliferator-activated receptor-associated genes. However, further work is needed to elucidate the possible mechanisms by which genistein and carnitine intervene.

Adipose Tissue↗

PubMed2006

Hypersensitivity of prediabetic JCR:LA-cp rats to fine airborne combustion particle-induced direct and noradrenergic-mediated vascular contraction.

Particulate matter with mean aerodynamic diameter < or =2.5 microm (PM(2.5)), from diesel exhaust, coal or residual oil burning, and from industrial plants, is a significant component of airborne pollution. Type 2 diabetes is associated with enhanced risk of adverse cardiovascular events following exposure to PM(2.5). Particle properties, sources, and pathophysiological mechanisms responsible are unknown. We studied effects of residual oil fly ash (ROFA) from a large U.S. powerplant on vascular function in a prediabetic, hyperinsulinemic model, the JCR:LA-cp rat. Residual oil fly ash leachate (ROFA-L) was studied using aortic rings from young-adult, obese, insulin-resistant rats and lean normal rats in vitro. Contractile response to phenylephrine and relaxant response to acetylcholine were determined in the presence and absence of L-NAME (N(G)-nitro-L-arginine methyl ester). In a separate series of studies, the direct contractile effects of ROFA-L on repeated exposure were determined. ROFA-L (12.5 microg ml(-1)) increased phenylephrine-mediated contraction in obese (p < 0.05), but not in lean rat aortae, with the effect being exacerbated by L-NAME, and it reduced acetylcholine-mediated relaxation of both obese and lean aortae (p < 0.0001). Initial exposure of aortae to ROFA-L caused a small contractile response (<0.05 g), which was markedly greater on second exposure in the obese (approximately 0.6 g, p < 0.0001) aortae but marginal in lean (approximately 0.1 g) aortae. Our data demonstrate that bioavailable constituents of oil combustion particles enhance noradrenergic-mediated vascular contraction, impair endothelium-mediated relaxation, and induce direct vasocontraction in prediabetic rats. These observations provide the first direct evidence of the causal properties of PM(2.5) and identify the pathophysiological role of the early prediabetic state in susceptibility to environmentally induced cardiovascular disease. These are important implications for public health and public policy.

Air Pollutants↗

PubMed2001

Effects of hyperinsulinemia and obesity on risk of neural tube defects among Mexican Americans.

Although both maternal obesity and diabetes mellitus increase the risk for neural tube defects, it is unknown whether they are independent risk factors or manifestations of an underlying prediabetic state such as hyperinsulinemia. We investigated whether hyperinsulinemia was a risk factor for neural tube defects independent of obesity and hyperglycemia in Mexican-American women. We identified case and control women from residents delivering or terminating pregnancies in hospitals or birthing centers in any of the 14 Texas-Mexico border counties during 1995-2000. Case women had a pregnancy affected by anencephaly, spina bifida, or encephalocele; randomly selected control women had normal births, frequency matched by year and birth facility. Questionnaire and laboratory values obtained 5-6 weeks postpartum were available for 149 case and 178 control women. Both hyperinsulinemia and obesity were related to increased neural tube defect risk [odds ratio (OR) = 1.91, 95% confidence interval (CI) = 1.21-3.01 and OR = 1.73, 95% CI = 1.03-2.92, respectively]. Adjustment for obesity only slightly reduced the effect of hyperinsulinemia (OR = 1.75, 95% CI = 1.09-2.82). Alternatively, a modest effect remained for obesity after adjustment for hyperinsulinemia (OR = 1.45, 95% CI = 0.84-2.51). Hyperinsulinemia is a strong risk factor for neural tube defects and may be the driving force for the observed risk in obese women.

Adult↗

PubMed2005

Epidemiology of the diabetic heart.

Diabetes mellitus is a worldwide epidemic. Cardiovascular disease remains the major cause of morbidity and mortality in people with diabetes. Studies have suggested that increased risk of cardiovascular disease is not restricted to type II or type I diabetes mellitus, but extends to prediabetic stages such as impaired fasting glucose, impaired glucose tolerance, metabolic syndrome, and obesity. Insulin resistance, impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus form a continuous sequence of risk for cardiovascular disease. Therefore, cardiovascular disease mortality and morbidity within the diabetes epidemic grow into vast proportions. Evidence also exists that diabetic patients have a high prevalence of heart failure or impaired diastolic and systolic cardiac function subsequent to the combination of coronary artery disease, hypertension, and diabetic cardiomyopathy. In view of the proportions of this new epidemic, prevention of diabetes and its prediabetic states is likely to be the most effective strategy to prevent serious cardiovascular events.

Clinical Trials as Topic↗

PubMed2005

Screening for kidney disease in adults with diabetes and prediabetes.

PURPOSE OF REVIEW: Worldwide, we are facing an increasing prevalence of diabetes mellitus, the number one cause of end-stage renal disease. It is imperative that chronic kidney disease among adults with diabetes mellitus be detected early when interventions are most effective in preventing end-stage renal disease. RECENT FINDINGS: Screening tools work best when health care providers have a clear understanding of the natural history of the disease process. The use of urine albumin measurement as a screening tool for diabetic nephropathy is based on the well characterized evolution of nephropathy in type 1 diabetes mellitus. However, the evolution of chronic kidney disease among adults with type 2 diabetes mellitus appears to be more heterogeneous. In contrast to type 1 diabetes mellitus, a substantial percentage of adults with type 2 diabetes mellitus have decreased glomerular filtration rate in the absence of increased urine albumin excretion. Focusing solely on urine albumin excretion to screen for chronic kidney disease may miss a substantial number of cases in adults with diabetes mellitus. In addition, up to one-third of adults with newly diagnosed diabetes mellitus already have chronic kidney disease, which may have first developed during the prediabetic state. Screening for chronic kidney disease only after an adult develops diabetes mellitus may miss that 'early' window of opportunity in many patients. SUMMARY: To maximize the effectiveness of our screening programs, we must not only use tests with adequate sensitivity but also implement screening tests early in the disease process to prevent the progression of chronic kidney disease to end-stage renal disease.

Adult↗