Long-term Hyperglycemia Research Articles

Higher arterial stiffness, greater peripheral vascular resistance and lower blood flow in lower‐leg arteries are associated with long‐term hyperglycaemia in type 2 diabetic patients with normal ankle‐brachial index

Higher arterial stiffness and greater peripheral vascular resistance reduce blood flow in lower-leg arteries and contribute to the development of ischaemic limb in diabetic patients even without peripheral artery occlusive disease. The aim of this study was to clarify whether these vascular parameters are associated with long-term hyperglycaemia in diabetic patients. We examined 45 type 2 diabetic patients and 38 age-matched nondiabetic subjects without peripheral artery occlusive disease assessed by ankle-brachial index consecutively admitted to our hospital, and followed them over a 3-year period (3.7 +/- 0.7 years) with no vasodilative medication. Blood flow and resistive index, a measure of peripheral vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulse wave velocity was measured to assess arterial stiffness. At baseline, consistent with our previous report, diabetic patients showed higher brachial-ankle pulse wave velocity (p < 0.0001) and resistive index (p < 0.0001) and lower flow volume (p = 0.0044) than those of nondiabetic subjects. Stepwise multiple regression analysis revealed that duration of diabetes, mean HbA(1c) during the study, use of renin-angiotensin system inhibitors and change per year in resistive index were identified as significant independent variables predicting change per year in blood flow (r(2) = 0.733, p < 0.0001) in diabetic patients. Mean HbA(1c) during the study was positively correlated with changes per year in brachial-ankle pulse wave velocity (p = 0.00007) and resistive index (p = 0.0014) and was negatively correlated with that in blood flow (p < 0.0001) in diabetic patients. Long-term hyperglycaemia is a major cause of impaired peripheral circulation in lower-leg arteries in diabetic patients without peripheral artery occlusive disease.

The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor

Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAFI). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAFI were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAFI showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAFI purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAFI in vitro on its function, TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAFI under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.

Safe Insulin Use in the Hospital Setting

Inpatients have a high rate of diabetes (12%-26%) and hyperglycemia (∼38%). All patients should have their glycosylated hemoglobin (A1c) checked on admission to help differentiate between long-term and new-onset hyperglycemia. Good glycemic control throughout the hospital stay is associated with decreases in short-and long-term risk of mortality, inpatient complications, length of hospital stay, and health care costs. Insulin is first-line therapy for hyperglycemia; patients with hyperglycemia should be managed using either intravenous (IV) or subcutaneous (SC) insulin algorithms. A hypoglycemia management protocol should be in place at the hospital for safety purposes. For successful glycemic control, insulin algorithms should have dynamic scales, require frequent glucose monitoring, and be simple and easy to use. The algorithm should address transitioning patients from IV to SC insulin and a discharge plan. Insulin analogues are preferred for basal, mealtime, and correction doses instead of human insulins (regular and NPH) because analogues have a more predictable absorption and action profile and less pharmacokinetic fluctuation. Institutions can increase safe insulin use by utilizing insulin algorithms, preprinted order sets, and hypoglycemia protocols; by supporting patient and health care provider education; and by implementing needle-stick prevention techniques.

Long-term hyperglycaemia impairs vascular smooth muscle cell function in women with type 1 diabetes mellitus

Observations of increased stiffness in the elastic aorta in women with diabetes, but not men, emphasise the need for further analysis regarding early abnormalities in arterial wall properties of women with type 1 diabetes mellitus (DM). Ultrasound was used to study the wall properties of the distal brachial artery (BA) in 37 type 1 diabetic women (aged 22-45 years) without evident complications and in 53 controls (C). Blood samples were drawn for later analysis. Flow-mediated dilatation (FMD) was slightly lower in DM than C, 8.1+/-4.3% vs. 10.3+/-4.9% (p<0.05), and nitrate-mediated dilatation (NMD) was markedly lower, 21.7+/-6.6% vs. 31.4+/-5.7% (p<0.001). Lumen diameter, intima-media thickness and distensibility were similar in DM and C. Insulin-like growth factor (IGF-1) was lower in DM than C, 231+/-65 vs. 349+/-68 ng/ml (p<0.001). Glycosylated haemoglobin (HbA1C) and matrix metalloproteinase (MMP-9) were independent predictors of the reduced NMD in the DM. Brachial artery responsiveness to an exogenous donor of nitric oxide (NO) was markedly reduced in type 1 diabetic women despite only limited reduction in endothelium-dependent dilatation. The negative association between NMD and HbA1C suggests that long-term hyperglycaemia impairs vascular smooth muscle cell function in DM.

Induction of Apoptosis of β Cells of the Pancreas by Advanced Glycation End‐Products, Important Mediators of Chronic Complications of Diabetes Mellitus

We herein report cytotoxicity of advanced glycation end-products (AGEs) on pancreatic beta cells. AGEs stimulated reactive oxygen species (ROS) generation but did not arrest proliferation of the INS-1 cell line. Pancreatic beta cell lines or primary cultured islets possess a receptor for AGE (RAGE), and its expression increased after AGE treatment. TUNEL staining and FACS analysis using annexin V/PI antibodies showed that apoptosis increased in INS-1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde (AGE2) or glucoaldehyde (AGE3), compared with those conjugated with glucose (AGE1). Reaction of INS-1 cells to Ki67, which is a cellular marker for proliferation, was also increased after AGE treatment. The ability of primary cultured islets to secrete insulin was retained even after AGE treatment under either low or high glucose conditions. The antiserum against RAGE partially prevented AGE-induced cellular events. Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes. AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets. Moreover, antibody array showed that RAD51 and RAD52 were significantly decreased in AGE2-treated INS-1 cells. AGEs might inhibit homologous DNA recombination for repairing DNA of INS-1 cells damaged by ROS generation. It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells. AGEs might deteriorate function of pancreatic beta cells in patients with long-term hyperglycemia.

Role of α-Lipoic Acid in Diabetic Polyneuropathy Treatment

Diabetic neuropathy represents late diabetes complications, and diabetes duration and long-term hyperglycemia are the main reasons for polyneuropathy. The goal was to estimate the effects of alpha-lipoic acid on symptoms of diabetic neuropathy after 600 mg i.v. for 3 weeks and 3 months of 300-600 mg of alpha-lipoic acid per os. This study has been designed as a multicentric, in 5-centers in B&H, carried out by 5 physicians with 20 diabetic patients each. Following parameters were monitored in 100 diabetics suffering from Type 1 and Type 2 diabetes, both men and women: diabetes duration, diabetes therapy, duration of polyneuropathy symptoms, height, weight, BMI (body mass index), subjective assessment of patients, objective examinations of physicians and subjective assessment of physicians. 100 diabetics, average age 61,36; oldest 79, youngest 40, suffered from diabetes in average 11,9 years. There were 35 men and 65 women, 16 with Type 1 and 80 with Type 2 diabetes, while 4 patients were not classified. 69 were having insulin therapy and 31 oral hypoglicemics. Shortest diabetic status was less than a year, and longest was 28 years. Average duration of polyneuropathic symptoms was 3,02 years, shortest was less than a year, and the longest was 15 years. Average height was 1,70 m, average weight 76,13 kg, and average BMI 26,51 kg/m2. Significant statistic differences in improvement were recorded (P>0,05) according to Fridman's test for repeated measurements compared to initial findings in assessments: sensory symptoms of polyneuropathy, pain sensations as polyneuropathy symptoms, total score of polyneuropathy symptoms, subjective assessment of patients, subjective findings of physicians, and significant differences were not find (P>0,05) in autonomous and motoric neuropathy. Based on the conducted study, we have concluded that the application of alpha-lipoic acid during 3 months has helped to decrease the symptoms of diabetic neuropathy and in only one case out of 100 included patients there was no subjective improvement after drug application.

Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure

Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the β-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

Silymarin as an Adjunct to Glibenclamide Therapy Improves Long-Term and Postprandial Glycemic Control and Body Mass Index in Type 2 Diabetes

Oxidative stress is increased postprandially and during long-term hyperglycemia in type 2 diabetic patients who present with poor response to glibenclamide. This study was designed to evaluate the effects of the antioxidant flavonoid silymarin in improving long-term and postprandial glycemic and weight control in type 2 diabetic patients treated with glibenclamide. Using a randomized, double-blind, placebo-controlled design, 59 type 2 diabetic patients, previously maintained on 10 mg/day glibenclamide and diet control, with poor glycemic control, were randomized into three groups: the first two groups were treated with either 200 mg/day silymarin or placebo as adjuncts to glibenclamide, and the third group was maintained on glibenclamide alone for 120 days. Fasting and 4-hour postprandial plasma glucose, glycated hemoglobin (HbA(1c)), and body mass index (BMI) were evaluated at baseline and after 120 days. Compared with placebo, silymarin treatment significantly reduced both fasting and postprandial plasma glucose excursions, in addition to significantly reducing HbA(1c) levels and BMI after 120 days. No significantly different effects were observed for placebo compared to glibenclamide alone. In conclusion, adjunct use of silymarin with glibenclamide improves the glycemic control targeted by glibenclamide, during both fasting and postprandially, an effect that may be related to increased insulin sensitivity in peripheral tissues.

AIR® Inhaled Insulin System: a novel insulin-delivery system for patients with diabetes

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® 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.

Delayed functional maturation of neonatal porcine islets in recipients under strict glycemic control

The aim of this study was to compare the functional maturation of neonatal porcine islet (NPI) grafts exposed to long-term hyperglycemia with those implanted under euglycemic conditions. mice Neonatal porcine islets were transplanted under the left renal capsule of diabetic SCID mice (group H), or in diabetic SCID mice who were also implanted with 500 BALB/c islets under the right renal capsule (group N). On day 42, the right kidneys were removed in both groups. No animals in group H achieved euglycemia within 3 weeks after transplantation. Thus, these mice were exposed to long-term hyperglycemia. Mice in group N became euglycemic immediately after transplantation, however after removal of BALB/c grafts on day 42 they exhibited significantly higher blood glucose levels than in group H and showed glucose intolerance after glucose administration. Cellular insulin content of NPI grafts harvested on day 58 or 72 was significantly lower in group N mice compared to group H. These results suggest that tight control of glycemia reduces the functional maturation of NPI grafts.

Subcellular characterization of glucose uptake in coronary endothelial cells

Despite all the evidence linking glucose toxicity to an increased risk of cardiovascular diseases, very little is known about the regulation of glucose uptake in endothelial cells. We have previously reported an asymmetric distribution of the GLUTs (1–5) and SGLT-1 in en face preparations of rat coronary artery endothelia [Gaudreault N., Scriven D.R., Moore E.D., 2004. Characterisation of glucose transporters in the intact coronary artery endothelium in rats: GLUT-2 upregulated by long-term hyperglycaemia. Diabetologia 47(12),2081–2092]. We assessed this time, through immunocytochemistry and wide field fluorescence microscopy coupled to deconvolution, the presence and subcellular distribution of glucose transporters in cultures of human coronary artery endothelial cells (HCAECs). HCAECs express GLUT-1 to 5 and SGLT-1, but their subcellular distribution lacks the luminal/abluminal asymmetry and the proximity to cell-to-cell junctions observed in intact endothelium. To determine the impact of the transporters' distribution on intracellular glucose accumulation, a fluorescent glucose analog (2-NBDG) was used in conjunction with confocal microscopy to monitor uptake in individual cells; the arteries were mounted in an arteriograph chamber with physiological flow rates. The uptake in both preparations was inhibited by cytochalasin-B and d-glucose and stimulated by insulin, but the distribution of the incorporated 2-NBDG mirrored that of the transporters. In HCAEC it was distributed throughout the cell and in the intact arterial endothelium it was restricted to the narrow cytosolic volume adjacent to the cell-to-cell junctions. We suggest that the latter subcellular organization and compartmentalization may facilitate transendothelial transport of glucose in intact coronary artery.

Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products

The epithelial sodium channel (ENaC) is a complex, and the alphaENaC subunit has a crucial role in sodium uptake induced by aldosterone in the distal nephron. Although experimental animal models of diabetes have demonstrated up-regulation of alphaENaC expression in renal cortical collecting duct (CCD) cells, the molecular mechanism remains unclear. Advanced glycation end products (AGEs) are by-products of long-term hyperglycaemia and comprise a significant pathogenic factor in diabetic nephropathy. We hypothesize that AGEs play a role in regulating alphaENaC gene expression. Mouse CCD cells (mpkCCDcl(4)) were cultured with AGE to determine the effects of AGE on alphaENaC expression and sodium uptake. Gene expressions of ENaC were measured by real-time PCR and sodium uptake was measured with fluorescent dye as a sodium indicator (SBFI-AM). This study analysed mitogen-activated protein kinases signalling pathways by western blotting. Cells co-transfected with plasmids of the alphaENaC promoter carrying a luciferase reporter and plasmids expressing wild-type or mutant serum- and glucocorticoid-induced kinase 1 (Sgk1) mRNA were stimulated with AGE to identify the signalling pathway. The AGEs, stimulated in a time- and dose-dependent manner, enhanced alphaENaC mRNA expression and sodium uptake in mpkCCDcl(4) cells. The AGEs also significantly stimulated Sgk1 mRNA and Sgk1 activity in a time- and dose-dependent manner. Co-transfected with plasmid expressing mutant Sgk1 significantly limited stimulated alphaENaC promoter-driven luciferase activity by AGEs in mpkCCDcl(4) cells. Experimental results indicate that AGEs induced alphaENaC expression and increased sodium uptake in renal CCD cells. The mechanism through which AGEs activate alphaENaC expression may be via activation of Sgk1 in mpkCCDcl(4) cells.

Plasma Ghrelin Concentrations in Different Clinical Stages of Diabetic Complications and Glycemic Control in Japanese Diabetics

Ghrelin is an acylated 28-amino-acid peptide that stimulates food intake, GH secretion, and gastric motility. Experimental studies have suggested that ghrelin plays roles in glucose homeostasis, atherosclerosis, and microangiopathy. We investigated possible involvement of ghrelin in micro- and macro-vascular diabetic complications and glycemic control in diabetic patients. Fasting and postprandial plasma ghrelin concentrations after a test meal were measured in 108 and 61 Japanese diabetic patients, respectively. Plasma ghrelin concentrations were negatively correlated with body mass index (BMI) (r = -0.309, P = 0.002) or HbA(1c) (r = -0.264, P = 0.0065). Plasma ghrelin levels in patients with diabetic nephropathy who showed high serum creatinine levels (s-Cre) were significantly higher than those in patients who showed normal s-Cre (P<0.02). In patients with diabetic triopathy, plasma ghrelin concentrations were significantly lower than those in patients without diabetic complications (P<0.05). Stepwise multiple regression analyses revealed that s-Cre, BMI, and HbA(1c) were independently associated with plasma ghrelin levels. A postprandial decrease of ghrelin was observed in patients with normal CV(R-R) values or those with normal body weight, whereas it was not seen in obese patients or in patients with low CV (R-R) values. Suppression rates of ghrelin 30-60 min after a test meal in obese patients were significantly lower than those in normal-weight patients. These findings suggest that ghrelin secretion is suppressed by long-term hyperglycemia and that obesity influences the regulation of ghrelin secretion.

Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin

Glycemic control and prevention of secondary complications are the most important goals of using pharmacologic treatment of diabetes mellitus (DM). The inadequate responses to oral hypoglycemic agents may be attributed to inadequate postreceptor events even when insulin levels are quite sufficient, and associated with oxidative stress induced by long-term hyperglycemia. The administration of antioxidants such as melatonin and zinc may improve tissue responses to insulin and increase the efficacy of drugs, e.g. metformin, which act through this pathway. This project was designed to evaluate the effects of melatonin and zinc on the lipid profile and renal function in type 2 DM patients poorly controlled with metformin. A placebo-controlled, double-blind clinical trial was performed in which 46 type 2 diabetic patients were selected and allocated into three groups. These groups were treated with single daily oral doses of both 10 mg of melatonin and 50 mg of zinc acetate alone: 10 mg of melatonin and 50 mg of zinc acetate in addition to the regularly used metformin or placebo, given at bedtime for 90 days. Fasting lipid profiles and microalbuminuria (MAU) were measured before initiating the treatments (zero time) and after 30 and 90 days of treatment. Daily administration of melatonin and zinc improved the impaired lipid profile and decreased the level of MAU; the addition of this treatment regimen in combination with metformin improved the tissue responses to this oral hypoglycemic agent. In conclusion, the combination of melatonin and zinc acetate, when used alone or in combination with metformin, improves DM-related complications such as the impaired lipid profile and MAU in type 2 DM patients.

Antioxidative enzyme and glutathione S-transferase activities in diabetic rats exposed to long-term ASA treatment

Low-dose acetylsalicylic acid (ASA) treatment is a standard therapeutic approach in diabetes mellitus for prevention of long-term vascular complications. The aim of the present work was to investigate the effect of long-term ASA administration in experimental diabetes on activities of some liver enzymes: glutathione peroxidase (GSHPx), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione S-transferase (GST). Blood glucose, glycated hemoglobin, as well as plasma ALT and AST activities increased in rats with streptozotocin-induced experimental diabetes. The long-term hyperglycemia resulted in decreased activities of GSHPx (by 26%), catalase (by 34%), GST (by 38%) and G6PDH (by 27%) in diabetic animals. We did not observe increased accumulation of membrane lipid peroxidation products or altered levels of reduced glutathione in livers. The linear correlation between blood glucose and glycated hemoglobin in diabetic animals was distorted upon ASA treatment, which was likely due to a chemical competition between nonenzymatic protein glycosylation and protein acetylation. The long-term ASA administration partially reversed the decrease in GSHPx activity, but did not influence the activities of catalase and GST in diabetic rats. Otherwise, some decrease in these parameters was noted in ASA-treated nondiabetic animals. Increased ASA-induced G6PDH activity was recorded in both diabetic and nondiabetic rats. While both glycation due to diabetic hyperglycemia and ASA-mediated acetylation had very similar effects on the activities of all studied enzymes but G6PDH, we conclude that non-enzymatic modification by either glucose or ASA may be a common mechanism of the observed convergence.

Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy

In addition to nephropathy, retinopathy and peripheral neuropathy, a microvascular complication of type 1 diabetes that may be tentatively referred to as 'diabetic encephalopathy' has gained increasing attention. There is growing evidence that lowered cognitive performance in patients with type 1 diabetes is related to chronic hyperglycaemia rather than recurrent episodes of severe hypoglycaemia, as previously speculated. The aim of our study was to use magnetic resonance imaging (MRI) to establish whether long-term hyperglycaemia, resulting in advanced retinopathy, contributes to structural changes in the brain (reduced grey matter). We applied voxel-based morphometry on magnetic resonance images to compare grey matter density (GMD) between three groups of participants. GMD is used as a marker of cortical atrophy. We compared 13 type 1 diabetic patients with a microvascular complication (i.e. proliferative retinopathy) with 18 type 1 diabetic patients who did not have retinopathy in order to assess the effects of microvascular changes on GMD. Both patient groups were compared with 21 healthy control subjects to assess the effect of diabetes in itself. Patients with diabetic retinopathy showed reduced GMD in the right inferior frontal gyrus and right occipital lobe compared both with patients without retinopathy and with healthy controls (p<0.05). Our data show that patients with type 1 diabetes, who, as a consequence of chronic hyperglycaemia, had developed advanced retinopathy, also showed increased focal cortical atrophy on brain MRI.

Advanced Diabetic Neuropathy: A Point of no Return?

Diabetic peripheral neuropathy is the most common complication of long-standing diabetes mellitus which frequently results in clinically significant morbidities e.g. pain, foot ulcers and amputations. During its natural course it progresses from initial functional changes to late, poorly reversible, structural changes. Various interconnected pathogenetic concepts of diabetic neuropathy have been proposed based on metabolic and vascular factors, mostly derived from long-term hyperglycemia. These pathogenetic mechanisms have been targeted in several experimental and clinical trials. This review summarizes available, mainly morphological data from interventions designed to halt the progression or achieve the reversal of established diabetic neuropathy, which include the recovery of normoglycemia by pancreas or islet transplantation, polyol pathway blockade by aldose reductase inhibitors, mitigation of oxidative stress by the use of antioxidants or correction of abnormalities in essential fatty acid metabolism. Unfortunately, to date, no treatment based on pathogenic considerations has shown clear positive effects and thus early institution of optimal glycemic control remains the only available measure with proven efficacy in preventing or halting progression of diabetic neuropathy. Further experimental and clinical research employing objective reproducible parameters is clearly needed. Novel non-invasive or minimally invasive methods e.g. corneal confocal microscopy or epidermal nerve fiber counts may represent potentially useful instruments for the objective assessment of nerve damage and monitoring of treatment effects.

Long-term sucrose-drinking causes increased body weight and glucose intolerance in normal male rats

The current epidemic of diabetes likely reflects marked changes in environmental factors, although genetic susceptibility plays a powerful role in the occurrence of diabetes in certain populations. We investigated whether long-term sucrose-drinking causes hyperglycaemia in male Wistar-Imamichi littermates (n 32), which are not genetically susceptible to diabetes or obesity. Each litter was divided equivalently into two groups, the sucrose group and the control group. The sucrose group received 300 g/l sucrose water and the control group received regular water until 42 weeks of age. Rats were weighed every 1 or 2 weeks. Oral glucose tolerance tests were performed at 28 and 36 weeks of age. Plasma glucose and insulin concentrations were measured. Body weights were significantly greater in the sucrose group than in the control group in 18-week-old rats (P<0.05), and the difference between the two groups reached 163 g by the end of the study (P<0.01). The 120 min post-load plasma glucose concentration in the sucrose group was 11.4 (SD 2.8) mmol/l in 28-week-old rats and 12.7 (SD 2.2) mmol/l in 36-week-old rats, while that of the control group remained approximately 7.3-7.7 mmol/l. In the sucrose group, the plasma insulin peak occurred 30 min post-load at 28 weeks of age; but the peak disappeared and hyperinsulinaemia was prolonged at 36 weeks of age. In conclusion, long-term sucrose-drinking causes increased body weight and glucose intolerance in normal male rats.

Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes

Intima media thickness (IMT) of the common carotid artery (CCA) is a validated surrogate marker of early atherosclerosis. The aim of our study was to assess the association between IMT in CCA and long-term mean HbA1c in type 1 diabetes. We also elucidated the association between carotid IMT and preclinical coronary atherosclerosis. In 39 individuals with type 1 diabetes, HbA1c was measured prospectively over 18 years. The IMT examinations were performed with high-resolution ultrasound. The association between carotid IMT and preclinical coronary atherosclerosis (assessed by intravascular ultrasound [IVUS]) was tested in 29 of the patients. Mean HbA1c over 18 years was 8.2% (range: 6.6-11.3%). Mean age at follow-up after 18 years was 43 years and mean duration of diabetes was 30 years. IMT was significantly higher in diabetic patients than in an age- and sex-matched reference population. The IMT values were at the same level as for controls who were 20 years older. In women, HbA1c was significantly associated with mean average CCA IMT (r2=0.77, p<0.0001 when adjusted for age), whereas there was no significant association for men. Among women, a significant association was also found between carotid IMT and the percentage of coronary vessel area stenosis (r=0.65, p=0.03). The present findings suggest an important role of long-term hyperglycaemia in the development of atherosclerosis, especially in women with type 1 diabetes. Type 1 diabetes patients have earlier development of, and more advanced, atherosclerosis compared with an age- and sex-matched reference population. In women, carotid IMT reflects preclinical coronary atherosclerosis.

Long-term treatment with the Na +-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats

We examined the effects of T-1095, an orally active inhibitor of Na +-glucose cotransporter (SGLT), on the development and severity of diabetes in Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of type 2 diabetes. T-1095 was administered as dietary admixture (0.1% w/w) beginning at 7 weeks of age for 32 weeks. Untreated male GK rats were hyperglycemic compared with Wistar rats. Throughout the study, T-1095 treatment significantly decreased both blood glucose and hemoglobin A 1C levels in the GK rats. The concomitant increase of urinary glucose excretion indicated that the hypoglycemic action of T-1095 is derived from the enhancement of urinary glucose disposal. Although food intake was not changed in the T-1095-treated rats, the body weight gain was retarded. T-1095 treatment partially ameliorated oral glucose tolerance but not the impaired glucose-induced insulin secretion. Homeostasis model assessment (HOMA) indicated the existence of insulin resistance in GK rats and a significant restoration by T-1095-treatment. There was a reduction of the thermal response in tail-flick testing following long-term hyperglycemia (diabetic neuropathy). Treatment of T-1095 significantly prevented the development of diabetic neuropathy in male GK rats. Sustained improvement of hyperglycemia and prevention of diabetic neuropathy by the T-1095-treatment provide further support the use of SGLT inhibitors for the treatment of diabetes.