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PubMed2005

Diazoxide attenuates insulin secretion and hepatic lipogenesis in zucker diabetic fatty rats.

BACKGROUND: Attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, in Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes and leptin resistance, decreased weight gain, improved lipid profile and prevented diabetes. Since the opposing effects of insulin and leptin regulate hepatic lipogenesis, we studied effects of insulin suppression on key insulin-sensitive genes regulating hepatic lipogenesis. MATERIAL/METHODS: DZ (150 mg/kg/day) or vehicle [pair-fed (PF) and control (C)] was administered to pre-diabetic obese ZDF and ZDF lean (ZL) rats for 8 weeks. RESULTS: Hepatic glucose transporter-2 protein expression decreased only in DZ-ZDF rats (p<0.001). However, insulin receptor substrate-1/2 protein expressions were enhanced in DZ-ZDF (p<0.02) and DZ-ZL (p<0.03) rats corresponding to increased phosphorylated protein kinase B levels in both strains (p<0.03). DZ increased glycogen synthase expression in ZDF (p<0.005) and ZL (p<0.002) rats. DZ reduced expression of sterol regulatory element-binding protein-1c, (p<0.0001), fatty acid synthase (p<0.002), acetyl CoA carboxylase (p<0.001), hormone-sensitive lipase (p<0.005), and peroxisome proliferator agonist receptor-gamma (p<0.02) in ZDF rats, without altering expressions of acyl CoA oxidase, peroxisome proliferator receptor-alpha, and carnitine palmitoyl transferase-1. DZ decreased hepatic triglycerides (p<0.001), long chain acyl-CoA (p<0.001) and cholesterol (p<0.01) contents only in ZDF rats, but increased glycogen content in both strains (p<0.02). CONCLUSIONS: Suppression of hyperinsulinemia by DZ enhanced hepatic insulin sensitivity and decreased expression of key genes regulating hepatic lipogenesis without altering genes regulating lipid oxidation; implying that attenuation of hyperinsulinemic state by DZ enhances metabolic efficiency of insulin and is therapeutically beneficial.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2005

Early pre-diabetic state alters adaptation of myocardial glucose metabolism during ischemia in rats.

Pre-diabetic subjects with high insulin secretory capacity have double risk of cardiovascular disease compared with subjects who do not develop insulin-resistance. It is well established that the ability of the myocardium to increase its glycolytic ATP production plays a crucial role in determining cell survival under conditions of ischemia. Up to now, whether the pre-diabetic state reduces the tolerance of the heart to ischemia by affecting its ability to increase its energy production through glycolysis remains unknown. The aim of the present study was to assess whether insulin resistance affects the ability of the myocardium to increase glycolysis under ischemic conditions. Male Wistar rats were fed for 8 weeks a fructose-enriched (33%) diet to induce a pre-diabetic state. Hearts were isolated and subjected to ex-vivo low-flow (2%) ischemia for 30 min. The fructose diet increased sarcolemmal GLUT4 localisation in myocardial cells under basal conditions compared with controls. This effect was not accompanied by increased glucose utilisation. Ischemia induced the translocation of GLUT4 to the plasma membrane in controls but did not significantly modify the distribution of these transporters in pre-diabetic hearts. Glycolytic flux under ischemic conditions was significantly lower in fructose-fed rat hearts compared with controls. The reduction of glycolytic flux during ischemia in fructose-fed rat hearts was not due to metabolic inhibition downstream hexokinase II since no cardiac accumulation of glucose-6-phosphate was detected. In conclusion, our results suggest that the pre-diabetic state reduces the tolerance of the myocardium to ischemia by decreasing glycolytic flux adaptation.

Adaptation, Physiological↗

PubMed1985

Prediction of type 1 diabetes mellitus--a report on three cases.

In three children (patients 1, 2 and 3) insulin-dependency was predicted 28, 32 and 4 months, respectively before the disease became clinically manifest, by the finding of islet cell antibodies at that time. These retrospective findings support the evidence for a long pre-diabetic phase in childhood diabetes, marked by the presence of islet cell antibodies, as well as the linkage of HLA-antigens to the susceptibility to this disease. The possibility of detecting pre-diabetic states in children before the endogenous insulin secretion decreases to the point of producing clinical symptoms support efforts by basic scientists to develop techniques for immunological intervention early in the course of the disease.

Adolescent↗

PubMed1980

Early insulin response in latent gestational diabetes.

The intravenous glucose tolerance and glucose-stimulated early insulin response (EIR) were studied in late pregnancy and post partum in a reference (R) group of 9 women and in 18 women with latent gestational diabetes (LD), defined as a k-value of < 0.66/h and a normal fasting blood glucose concentration. During pregnancy, the LD group showed a lower EIR than the R group. However, the response ranged between normal and non-detectable. In the non-pregnant state, the EIR was the same in the two groups. The inability to increase the EIR during pregnancy wss most evident in women who even post partum had an abnormal glucose tolerance. In some women in the LD group, the EIR during pregnancy was even lower than in the non-pregnant state. The magnitude of the response in the non-pregnant state was not decisive of the capacity to increase the secretion during pregnancy. None of the women in the LD group developed manifest diabetes during pregnancy. They gave birth to children with normal birth weight, and no neonatal problems were registered except for one child with congenital heart malformation.

Adult↗

PubMed1987

[Use of a method for assessing the glucose tolerance test by a generalized criterion in detecting the early stages of diabetes mellitus in the universal dispensary care of the population].

Assessment of the glucose tolerance test based on a generalized criterion permits the diagnosis of early carbohydrate metabolic derangements and an analysis of the carbohydrate metabolic state with respect to any trait of interest. The use of the generalized criterion during mass screening gives an opportunity to attribute examinees to one or another sociomedical group, to assess the results of primary preventive measures of diabetes mellitus both among healthy persons and those with risk factors, with disturbed glucose tolerance.

Algorithms↗

PubMed2005

Diabetes and schizophrenia 2005: are we any closer to understanding the link?

The association between schizophrenia and diabetes has been recognized for well over a century, but the underlying reasons for this association are unclear. In October 2003, an international group of diabetologists and psychiatrists met to review the literature relating to the association, and to create pragmatic guidelines for the management of diabetic risk in patients with severe mental illness. Since that meeting, over 100 additional papers have been published on the association between glucose abnormalities and schizophrenia, and this is a clear reflection of the level of interest in this clinically important area. Diabetes is highly prevalent among the schizophrenia population, but most sufferers remain undiagnosed in the community. The reasons why individuals with schizophrenia are more prone to developing diabetes than the general population are poorly defined, but likely to be multifactorial. The role of antipsychotic medications in the development of diabetes and other pre-diabetic states remains controversial, but it appears that the attributable risk is low. Traditional risk factors most probably account for much of the diabetes seen in schizophrenia populations, suggesting that routine screening and aggressive risk factor management are especially important in this patient group.

Antipsychotic Agents↗

PubMed2004

Diabetes in the Hispanic population. High risk warrants targeted screening and treatment.

As the Hispanic population in the United States increases, more primary care physicians are being challenged to address the high incidence of diabetes and related metabolic disorders in Hispanic American patients. A variety of genetic, environmental, and socioeconomic factors contribute to this group's high susceptibility to diabetes. In this article, Drs Idrogo and Mazze discuss diagnosis of diabetes in Hispanic patients, as well as culturally sensitive screening and treatment strategies.

Adolescent↗

PubMedDate not supplied

[State of the microcirculation in the relatives of diabetes mellitus patients].

The biomicroscopic study of the conjunctival vessels demonstrated microcirculation disturbances in 43.8% of 105 relatives of diabetic patients, and in 8.5% changes of the optic fundus vessels, irrespective of the glucose tolerance test results. There was a statistically significant difference between the total conjunctival index and its partial values in the relatives of diabetic patients in comparison with the control (healthy) group, and in patients with newly diagnosed diabetes mellitus as compared with the control group and with the group of relatives with a normal glucose tolerance test.

Adolescent↗

PubMed1985

Diabetes and impaired glucose tolerance. A prevalence estimate based on the Busselton 1981 survey.

We have estimated the prevalence of diabetes and impaired glucose tolerance from the Busselton 1981 Population Survey using the 1980 World Health Organization (WHO) criteria. Standardized to the Australian non-Aboriginal population aged 25 years and over, the prevalence rates in this white community were 2.5% for known diabetes; 0.9% for newly discovered diabetes; 2.9% for impaired glucose tolerance; and 6.3% for all categories of abnormal glucose tolerance. There appears to have been a real increase in the frequency of diabetes since 1966. Using fasting serum C-peptide values and clinical criteria, 14% of all diabetic subjects were insulin-dependent. The male:female ratio for all categories of abnormal glucose tolerance was 1.4:1. Data from the United States indicate spectacularly higher rates for diabetes and impaired glucose tolerance in the white population. A national study of the prevalence of diabetes and impaired glucose tolerance in Australia is recommended. For epidemiological purposes, a single blood glucose value two hours after a 75 g oral glucose tolerance test is sufficient to categorize glucose tolerance as defined by WHO.

Adult↗

PubMed2006

Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport.

Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myotubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by approximately 2-fold. In contrast, a hyperinsulinemic state, induced by inclusion of 5 nM insulin in the medium for 12 h decreased the ability of insulin to stimulate these processes. Defects in insulin signaling did not readily account for the observed disruption. In contrast, hyperinsulinemia reduced cortical F-actin. This occurred concomitant with a loss of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)), a lipid involved in cytoskeletal regulation. Restoration of plasma membrane PIP(2) in hyperinsulinemic cells restored F-actin and insulin responsiveness. Consistent with these in vitro observations suggesting that the hyperinsulinemic state negatively affects cortical F-actin structure, epitrochlearis skeletal muscle from insulin-resistant hyperinsulinemic Zucker fatty rats displayed a similar loss of F-actin structure compared with that in muscle from lean insulin-sensitive littermates. We propose that a component of insulin-induced insulin resistance in skeletal muscle involves defects in PIP(2)/F-actin structure essential for insulin-regulated glucose transport.

Actin Cytoskeleton↗

PubMed2006

Mathematical beta cell model for insulin secretion following IVGTT and OGTT.

Evaluation of beta cell function is conducted by a variety of glucose tolerance tests and evaluated by a number of different models with less than perfect consistency among results obtained from different tests. We formulated a new approximation of the distributed threshold model for insulin secretion in order to approach a model for quantifying beta cell function, not only for one, but for several different experiments. Data was obtained from 40 subjects that had both an oral glucose tolerance test (OGTT) and an intravenous tolerance test (IVGTT) performed. Parameter estimates from the two experimental protocols demonstrate similarity, reproducibility, and indications of prognostic relevance. Useful first phase indexes comprise the steady state amount of ready releasable insulin A0 and the rate of redistribution krd, where both yield a considerable correlation (both r=0.67) between IVGTT and OGTT estimates. For the IVGTT, A0 correlates well (r=0.96) with the 10 min area under the curve of insulin above baseline, whereas krd represents a new and possibly more fundamental first phase index. For the useful second phase index gamma, a correlation of 0.75 was found between IVGTT and OGTT estimates.

Adult↗

PubMed2006

Acarbose improves fibrinolytic activity in patients with impaired glucose tolerance.

Acarbose has been shown to ameliorate insulinemia, suggesting that it may exert favorable effects on the impaired fibrinolytic state in prediabetic patients. We therefore conducted a randomized controlled study to examine the effects of acarbose on fibrinolysis in patients with impaired glucose tolerance (IGT). The participants were randomized to receive (n = 20) or not (control, n = 20) 100 mg of acarbose before each meal (300 mg/d) for 3 months. A marked decrease in the plasma levels of plasminogen activator inhibitor 1 (by 42%) and fibrinogen (by 27%) was observed in the acarbose group at the end of the study, whereas no significant changes in the levels of these parameters were observed in the control group. We also conducted postprandial evaluation of insulin-related clinical markers and found ameliorated hyperinsulinemia in the subjects treated with acarbose. These results indicate that acarbose could improve fibrinolysis in patients with IGT, mainly by ameliorating insulinemia. Other favorable effects of acarbose, such as reduction in the plasma levels of oxidized low-density lipoprotein, glucose toxicity, and hyperglycemia, might also contribute, at least in part, to the beneficial effects of the drug on the fibrinolytic state in patients with IGT.

Acarbose↗

PubMed2005

Morphological pre-conditions of diabetes mellitus' development under chronic lipid-loading during aging.

Chronic lipid loading in pancreatic beta-cells of young and old animals causes the intensification of secretion the morphologic equivalents of which are revealed by elevation of number and sizes of mitochondria, granular endoplasmatic reticulum and Golgi apparatus of beta-cells with the quantitative increase of intraorganelle ultrastructures and decrease of volume share and number of secretor granules, which are more prominent in old animals. After definitive period following the chronic lipid loading the secretor processes in young age are normalized (organelles turn back to their initial volume state and consist of the same initial number of intraultrastructures), whereas in old age -- are markedly lower compared with the norm (size and number of organelles and their inner structures are decreased; volume part of secretory granules is increased); in some part of beta-cells complete block of secretion takes place (in the part of beta-cells the irreversible changes are developed; stagnation of secrete is prominent). Therefore any metabolic disease or syndrome running on the background of chronic lipidemia, seems to be a risk-factor for development of Diabetes Mellitus in organisms of old age.

Aging↗

PubMed1975

Emergence of overt diabetes in offspring of rats with induced latent diabetes.

A single subdiabetogenic dose of alloxan administered to the weanling rat induces a persistent state of latent diabetes which progresses to fasting hyperglycemia by the seventh generation. Initial descendants of alloxan-treated animals have hyperinsulinism which progresses to insulinopenia in later generations. Later generation animals develop ketoacidosis when challenged with a dose of alloxan that has no effect on control animals. The significant sex difference in glucose tolerance rates disappears as the animals become more diabetic and decreased fertility and parity become apparent. One explanation for this data remains the hypothesis of paramutation, induced by alloxan, affecting regulator gene activity. Light microscopy of diabetic animals shows no pathology.

Animals↗

PubMed1977

[Pregnancy and diabetes].

There is a mutual effect between gravidity and diabetes. Diabetes can have disadvantageous effect over gravidity, but the state of gravidity can contribute to the earlier diagnosis of diabetes. The author had 4850 cases of gravidity of 1686 women, indiscriminately, suffering from diabetes observed and on the basis of his observation he found that the manifestations of diabetes in the state of gravidity are respectively infrequent nowadays but the number of manifestation increases parallel with the fatness of women. The transitional diabetogen effect, the pathologic gravidities and the huge-embryos are, however, able to indicate the early stage of diabetes, that other methods or medical examinations could not still indicate. The birth of huge-embryos is the earliest and most characteristic praediabetic sign and it can appear 30 to 50 years before the development of diabetic trouble of metabolism. The number of pathological gravidities increases parallel with the advance of diabetic manifestation. The author emphasises on basis of his observations the importance of obstetrical and pregnancy-anamnesis in the prevention of diabetic manifestation and in the reduction of foetal losses.

Adult↗

PubMed1985

Long-range implications for the mother. The Aberdeen experience.

One hundred twelve women with impaired glucose tolerance (IGT) diagnosed by intravenous glucose tolerance test (IVGTT) after pregnancy were followed up for a period of up to 22 yr (mean 12.9 yr). About one-third have been treated with chlorpropamide and the others by diet only. At the final assessment, approximately 35% had abnormal intravenous glucose tolerance and less than 7% overt diabetes. Chlorpropamide did not prove significantly more effective than diet only. Factors associated with deterioration in glucose tolerance were age at diagnosis and follow-up and the initial fasting plasma glucose (FPG) level (greater than or equal to 5.8 mM), but obesity was less important, although it was associated with an increased rate of vascular complications. Tests for islet cell antibodies (ICA) were weakly positive in 12.5% of 72 subjects and in only 0.5% of an unselected population; they did not correlate with the final state of glucose tolerance. Only three patients developed insulin-dependent diabetes (IDDM) and did so before the ICA study was started. A comparison is made between the results reported by O'Sullivan in patients diagnosed as having gestational diabetes, only 2% of whom still had abnormal oral glucose tolerance postpartum, and the results of our patients, all of whom had IGT after pregnancy. In spite of differences of technique and in the populations studied, the prevalence of IGT and overt diabetes at follow-up was significantly less in the Aberdeen series, who were initially a higher risk group. It seems probable that this is mainly attributable to dietary treatment in the follow-up period as O'Sullivan's cases were treated only during pregnancy.

Adolescent↗

PubMed1994

The paternally inherited insulin gene B allele (1,428 FokI site) confers protection from insulin-dependent diabetes in families.

Several polymorphisms of the insulin gene and its flanking regions (INS region) are in linkage disequilibrium and confer susceptibility to insulin-dependent diabetes (IDDM). We have analysed INS AA and AB-BB genotypes at the 1,428 FokI site (3' of the insulin gene) in 217 patients with IDDM, 402 non-diabetic first degree relatives negative for insulin (IAA) and islet cell autoantibodies (ICA), and 116 autoantibody positive (for ICA or IAA, or both) relatives of whom 39 became diabetic on follow-up. Most IDDM patients (83.4%, 181/217) had the AA genotype vs. 50% (25/50) of the controls (P < 10(-6)). Only 16.6% (36/217) of IDDM patients carried the AB genotype and none was BB homozygous, suggesting a protective effect of the B allele. By segregation analysis of the B allele in the IDDM offspring of informative families (only one AB parent) from the United States, the maternal B allele was inherited by 19/35 (54.2%) of the IDDM offspring. In contrast, only 4/26 (15.3%) of the IDDM offspring inherited the paternal B allele (P = 0.001), suggesting maternal imprinting of the INS region. Therefore, the INS B allele may be protective only when paternally inherited. Among the 39 of 116 autoantibody positive relatives who developed IDDM on follow-up, only five of them had the B allele. The frequency of the B allele in this group was much lower (12.8%, 5/39) than that observed in non-diabetic autoantibody positive relatives (32.5%, 25/77, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2003

Is microvascular flow rate related to ghrelin, leptin and adiponectin levels?

Ghrelin, leptin and adiponectin are three hormones which are frequently associated with metabolism, obesity and appetite. Recently, it has been shown that they may possess other physiologic roles, specially in connection with the circulation. Ghrelin infusion increases forearm blood-flow in a dose-dependent manner. Leptin has been shown to be involved not only in thermogenesis but angiogenesis as well. Adiponectin, apart from its insulin-sensitizing action, appears to modulate inflammation by inhibiting monocyte adhesion to endothelial cells. Six monkeys, which had been classified as being in the pre-diabetic state, where administered a triglyceride lowering regimen. Microvascular function was assessed using a laser Doppler flow-meter during a temperature provocation test. Percent change in flow from baseline following temperature elevation, as well as percent change in flow/degree rise in temperature were used to evaluate microvascular reserve and reactivity. Using univariate analysis, it appears that increased perfusion is significantly correlated with adiponectin, followed by leptin. Flow was also positively correlated with ghrelin, but the relationship did not attain significance. As expected, flow was also negatively and significantly correlated with fibrinogen. Trends show that flow was also negatively correlated to circulating triglyceride levels (p=0.08). The data indicate that the three hormones appear to possess microvascular actions that may impact on their other physiologic functions.

Adiponectin↗