Fasting Normoglycemia Research Articles

Fasting Normoglycemia after Intravenous Thrombolysis Predicts Favorable Long-Term Outcome in Non-Diabetic Patients with Acute Ischemic Stroke.

Background: Only a few studies evaluated the role of fasting glucose levels after intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS). Importantly, formal analysis concerning the prognostic role of fasting glucose levels in these patients with and without diabetes mellitus (DM) was not performed. Therefore, we assessed whether fasting normoglycemia (FNG) next morning after AIS treated with IVT was associated with 90-day functional outcome in diabetic and non-diabetic patients. Methods: We retrospectively analyzed 362 AIS patients treated with IVT at The University Hospital in Krakow. FNG was defined as glucose below 5.5 mmol/L. A favorable outcome was defined as modified Rankin score (mRS) of 0–2 at day 90 after AIS onset. Results: At 3-month follow-up, FNG was associated with favorable outcome (87.5% vs. 60.8%, p < 0.001) and decreased risk of death (3.1% vs. 18.1%, p = 0.002). Independent predictors of a favorable outcome for the whole group were: younger age (HR 0.92, 95%CI 0.89–0.95), lower NIHSS score after IVT (HR 0.70, 95%CI 0.65–0.76), lower maximal systolic blood pressure within 24 h after IVT (HR 0.92, 95%CI 0.89–0.95) and FNG (HR 4.12, 95%CI 1.38–12.35). Association between FNG and mortality was found in univariable (HR 1.47, 95%CI 0.04–0.62) but not in multivariable analysis (HR 0.23, 95%CI 0.03–1.81). In subgroup analyses, FNG was an independent predictor of favorable outcome (HR 5.96, 95%CI 1.42–25.1) only in patients without DM. Conclusions: FNG next morning after IVT is an independent protective factor for a favorable long-term outcome in non-diabetic AIS patients.

Analysis of the formation of dysglycemia in the substantiation of early pathogenetic therapy of diabetes mellitus

Introduction. To control carbohydrate metabolism disorders (CMD), which are closely related to the effect on the prognosis of cardiovascular diseases (CVD), their early, pathogenetically substantiated and prognosis-oriented therapy is required with a view to positive metabolic memory. The choice of drugs is based on the analysis of the formation of pre-nosological CMD - variants of prediabetes. The indices of the homeostatic model HOMA and the TyG family are most often used to assess the main links in the pathogenesis of CMD, IR and the secretory capacity of β-cells.Objective: to assess the basic pathogenetic links in prenosological CMD in comparison with type 2 diabetes mellitus (DM2) using a cohort of postmenopausal women: parameters of IR and secretory capacity of β-cells according to the TyG and HOMA-2 indices. Materials and methods. The examined 94 postmenopausal women 58.0 (53.0; 63.0) years old were divided into groups by history and HbA1c levels (%). Group 1 consisted of patients with T2DM (7.20: 6.60; 7.98) with a duration of 4.0 (2.0; 7.0) years; women with two-fold fasting normoglycemia without a history of CMD were classified according to their HbA1c levels into group 2 (prediabetes) and 3 (without CMD) twice: according to WHO criteria - 6.15 (6.03; 6.30) and 5.45 (5.20; 5.80); and ADA - 6.00 (5.80; 6.23) and 5.35 (5.05; 5.40), respectively. The indices TyG, HOMA2-IR, HOMA2-%S, and HOMA2-%B were determined (based on C-peptide calculations).Results and discussion. The performed analysis confirms the contribution of IR/insulin sensitivity to the progression of CMD with the participation of the phenomenon of lipoglucotoxicity at the prenosological stage of their formation, starting with HbA1c ≥ 5.7% levels. The inadequate secretory response of β-cells reflects an early decline in their functional abilities even at the stage of prediabetes. This limits the effectiveness of the classical stepwise scheme for intensifying glucose-lowering therapy with a T2DM duration of less than 10 years.Conclusions. Along with the timely diagnosis of dysglycemia, to control the cardiometabolic risk, it is advisable to use drug combinations early in terms of their effect on the key links in the pathogenesis of CMD: insulin resistance and β-cell dysfunction. Pioglitazone has been substantiated as an insulin sensitizer, which has a proven effect on the regression of early CMD and a decrease in the risk of cardiovascular events. In order to eliminate incretin dysfunction, which is closely related to the adequacy of the secretory capabilities of β-cells to the needs of impaired glucose homeostasis, a rational combination with an inhibitor of dipeptidyl peptidase-4.

Features of Bcl2 and p53 proteins synthesis in pancreatic islets of normotensive and hypertensive rats with streptozotocin-induced diabetes

In our previous studies it was established that the remodeling of pancreatic islets with decreasing β-cell population density is formed in hypertensive SHR rats. The imbalance between the synthesis of proapoptotic and antiapoptotic factors may be one of the possible causes of disturbed formation of the endocrinocyte population in the pancreas. The aim of the research was to study the parameters of Bcl2 and p53 proteins synthesis in pancreatic islets in normotensive and hypertensive rats in the streptozotocin-induced diabetes mellitus development. Materials and methods . The study was performed on 30 normotensive male Wistar rats (systolic BP=105.0 ±1.1 mm Hg) and 25 hypertensive SHR rats (systolic BP=155.7 ±0.9 mm Hg) with fasting normoglycemia (4.73 ± 0.10 mmol/l). Bcl2 and p53 proteins were detected in histological pancreas sections by immunofluorescence method. The relative area of Bcl2- and p53-immunopositive material, concentration of proteins in endocrinocytes, their content in the islets and apoptosis index p53/Bcl2 were analyzed in pancreatic islands. Results. The area of relative immunofluorescence to the Bcl2 protein was 2 times less, and the protein content was 3 times lower in pancreatic islets of hypertensive rats (SHR) compared with normotensive Wistar rats. At the same time, no statistical differences in the area of the immunopositive material to the p53 protein and its content in the islets between the experimental groups were revealed. The development of streptozotocin-induced diabetes in Wistar rats was accompanied by approximately 2-fold decrease in the Bcl2 protein expression in pancreatic islets, a significant increase in the specific content of p53 protein and a 3.8-fold increase in the apoptosis index of p53/Bcl2. In pancreatic islets of SHR rats, diabetes mellitus development was accompanied by 2-fold increase in the specific content of the proapoptotic protein p53 without the reduction of the antiapoptotic protein Bcl2 synthesis. At the same time, the p53/Bcl2 apoptosis index in SHR rats remained statistically higher than in Wistar rats. Conclusions. Endocrine cells of pancreatic islets of SHR rats are characterized by the prevalence of proapoptotic protein p53 expression as compared with Wistar line normotensive rats. The development of streptozotocin diabetes in Wistar rats leads to a significant decrease in the number of endocrinocytes synthesizing the antiapoptotic protein Bcl2. At the same time, an increase in the synthesis of the proapoptotic protein p53 in endocrinocytes in diabetes is observed both in normotensive and in hypertensive rats.

Insulin resistance and cardiovascular outcomes in the ORIGIN trial.

In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (Clinicaltrials.gov: NCT000069784), titrated doses of basal insulin glargine targeting fasting normoglycaemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycaemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes. Self-titration of insulin doses targeting a fasting plasma glucose ≤5.3 mmoL/L (95 mg/dL) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose-lowering oral agent at randomization. Normoglycaemia was defined as a fasting plasma glucose <5.6 mmol/L and HbA1c <6% at the 2-year visit. The median of the natural logarithm of insulin doses (expressed per kg of fat-free mass), recorded at every visit from randomization until either the penultimate visit or the first occurrence of a cardiovascular outcome, was analysed. Higher median insulin doses did not reflect incident cardiovascular events overall or in the subset that achieved normoglycaemia. When the dose taken before a cardiovascular event or the penultimate visit was analysed, the adjusted hazard of the composite of cardiovascular death, myocardial infarction or stroke was 0.94 (95% CI 0.88, 1.00) per unit higher dose overall, and 0.91 (95% CI 0.81, 1.01) in the normoglycaemic subset. Insulin resistance may not promote cardiovascular outcomes in individuals with dysglycaemia.

Effect of Intensive Versus Standard Blood Pressure Treatment According to Baseline Prediabetes Status: A Post Hoc Analysis of a Randomized Trial.

To determine whether the effects of intensive (<120 mmHg) compared with standard (<140 mmHg) systolic blood pressure (SBP) treatment are different among those with prediabetes versus those with fasting normoglycemia at baseline in the Systolic Blood Pressure Intervention Trial (SPRINT). This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose <100 mg/dL). The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment among those with prediabetes and normoglycemia. Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively (P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia (P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05). In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia.

Glucose and Lipid Dysmetabolism in a Rat Model of Prediabetes Induced by a High-Sucrose Diet.

Glucotoxicity and lipotoxicity are key features of type 2 diabetes mellitus, but their molecular nature during the early stages of the disease remains to be elucidated. We aimed to characterize glucose and lipid metabolism in insulin-target organs (liver, skeletal muscle, and white adipose tissue) in a rat model treated with a high-sucrose (HSu) diet. Two groups of 16-week-old male Wistar rats underwent a 9-week protocol: HSu diet (n = 10)—received 35% of sucrose in drinking water; Control (n = 12)—received vehicle (water). Body weight, food, and beverage consumption were monitored and glucose, insulin, and lipid profiles were measured. Serum and liver triglyceride concentrations, as well as the expression of genes and proteins involved in lipid biosynthesis were assessed. The insulin-stimulated glucose uptake and isoproterenol-stimulated lipolysis were also measured in freshly isolated adipocytes. Even in the absence of obesity, this rat model already presented the main features of prediabetes, with fasting normoglycemia but reduced glucose tolerance, postprandial hyperglycemia, compensatory hyperinsulinemia, as well as decreased insulin sensitivity (resistance) and hypertriglyceridemia. In addition, impaired hepatic function, including altered gluconeogenic and lipogenic pathways, as well as increased expression of acetyl-coenzyme A carboxylase 1 and fatty acid synthase in the liver, were observed, suggesting that liver glucose and lipid dysmetabolism may play a major role at this stage of the disease.

Future challenges and therapeutic opportunities in type 2 diabetes: Changing the paradigm of current therapy.

Most algorithms for type 2 diabetes mellitus (T2DM) do not recommend treatment escalation until glycated haemoglobin (HbA1c) fails to reach the recommended target of 7% (53 mmol/mol) within approximately 3 months on any treatment regimen (“treat to failure”). Clinical inertia and/or poor adherence to therapy contribute to patients not reaching glycaemic targets when managed according to this paradigm. Clinical inertia exists across the entire spectrum of anti‐diabetes therapies, although it is most pronounced when initiating and optimizing insulin therapy. Possible reasons include needle aversion, fear of hypoglycaemia, excessive weight gain and/or the need for increased self‐monitoring of blood glucose. Studies have suggested, however, that early intensive insulin therapy in newly diagnosed, symptomatic patients with T2DM with HbA1c >9% (75 mmol/mol) can preserve beta‐cell function, thereby modulating the disease process. Furthermore, postprandial plasma glucose is a key component of residual dysglycaemia, evident especially when HbA1c remains above target despite fasting normoglycaemia. Therefore, to achieve near normoglycaemia, additional treatment with prandial insulin or a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) is often required. Long‐ or short‐acting GLP‐1 RAs offer effective alternatives to basal or prandial insulin in patients inadequately controlled with other therapies or basal insulin alone, respectively. This review highlights the limitations of current algorithms, and proposes an alternative based on the early introduction of insulin therapy and the rationale for the sequential or fixed combination of GLP‐1 RAs with insulin (“treat‐to‐success” paradigm).

Diabetes Exacerbates Coronary Atherosclerosis in Ossabaw Miniature Swine with Metabolic Syndrome

Over 35% of all US adults are estimated to have metabolic syndrome (MetS), which is defined as the presence of three or more of the following risk factors: obesity, hypertension, glucose intolerance, insulin resistance, and dyslipidemia. Furthermore, the incidence of type 2 diabetes is rapidly growing, often in an overlapping population. MetS and diabetes both substantially increase the risk of coronary artery disease (CAD), which continues to be the leading cause of death in the US. We investigated the extent to which diabetic hyperglycemia superimposed on MetS exacerbates CAD. We performed this study in the well‐characterized Ossabaw miniature swine model of MetS and CAD. The beta‐cell toxin alloxan was administered to swine by intravenous injection, then swine were placed in two groups: pigs that responded only transiently to alloxan thereafter having fasting normoglycemia (MetS, n=8) and those that responded to alloxan becoming permanently diabetic (MetS/D, n=8). After alloxan administration, swine were fed an atherogenic diet for six months to induce the MetS phenotype. At sacrifice, we used intravascular ultrasound (IVUS) imaging to quantify the extent of CAD by assessment of percent plaque burden and spotty calcification in the left anterior descending artery. Percent plaque burden quantifies the percentage of the area within the external elastic membrane (EEM) that is occupied by atherosclerotic plaque, using the formula (EEM area – lumen area)/EEM area*100%. The percent plaque burden was significantly greater in left anterior descending artery of the MetS/D swine compared to MetS swine (12.9% vs. 3.7%; p&lt;0.05). Furthermore, this difference was more prominent in the proximal 15 mm of the artery (17.1% vs. 3.9%; p&lt;0.05). We assessed coronary artery calcification by identifying echogenic signal stronger than adventitia and with acoustic shadowing peripheral to the calcium deposit. We calculated a calcium index for each artery using the formula (Frames with calcification/Total frames analyzed)*(Maximal arc angle of calcium/360°). The calcium index was significantly greater in the proximal 15 mm of the left anterior descending artery of MetS/D swine compared to MetS swine (0.0204 vs. 0.00003; p&lt;0.05). These results show significant positive correlation with Von Kossa stained sections from the proximal 15 mm of each vessel and analyzed for calcified area (r=0.84). Thus, we conclude that CAD, as measured by plaque burden and presence of calcification by IVUS, is exacerbated when diabetes is superimposed on MetS.Support or Funding InformationThis work was supported by NIH T35 HL110854, P30 DK097512, the Fortune‐Fry Ultrasound Research Fund, and Eli Lilly &amp; Co.

The distribution of the islets of Langerhans in pancreas of euglycemic spontaneously hypertensive rats

Учитывая то, что панкреатические бета-клетки ответственны за производство всего инсулина, необходимого организму для поддержания глюкозного гомеостаза, проблема контроля пула бета-эндокриноцитов у пациентов с гипертонической болезнью является актуальной, так как не исключено, что генетические дефекты формирования наследственной артериальной гипертензии развития могут затрагивать механизмы поддержания клеточной массы эндокриноцитов в поджелудочной железе и приводить к нарушению метаболизма глюкозы и диабету. Кроме того, к нарушению адекватной секреции инсулина поджелудочной железой может приводить нарушение цитоархитектоники панкреатических островков, что может быть спровоцировано региональными нарушениями кровообращения у пациентов с артериальной гипертензией. Цель работы – изучить параметры распределения панкреатических островков в поджелудочной железе у гипертензивных крыс линии SHR. Материалы и методы. Измерили уровень глюкозы в крови и концентрацию инсулина, а также анализ иммунофлюоресцентной реакции. Полученные данные обрабатывали пакетом статистических программ, для оценки достоверности различий в группах применяли t-критерий Стьюдента. Результаты. Морфометрический анализ показал, что у гипертензивных крыс линии SHR 78,8% панкреатических островков поджелудочной железы представлены маленькими островками, тогда как у нормотензивных крыс линии Wistar их доля составляет 44,3%. Обращает внимание большое количество единичных бета-эндокриноцитов в поджелудочной железе крыс линии SHR и полное отсутствие крупных островков. Вместе с тем уменьшение численности бета-клеток в железе у крыс линии SHR в значительной мере компенсировалось более высокой концентрацией иммунореактивного инсулина в эндокриноцитах, что, вероятно, обеспечивало сохранение достаточного уровня иммунореактивного инсулина в периферической крови и поддержание эугликемических показателей натощак. Выводы . Цитоархитектоника поджелудочной железы у гипертензивных крыс линии SHR характеризуется нарушением распределения панкреатических островков и доминированием малых островков. Бета-клетки у нормогликемических гипертензивных крыс линии SHR характеризуются в 2 раза более высокой, чем у номотензивных крыс линии Wistar, концентрацией иммунореактивного инсулина.

Glucose intolerance associated with hypoxia in people living at high altitudes in the Tibetan highland

ObjectivesTo clarify the association between glucose intolerance and high altitudes (2900–4800 m) in a hypoxic environment in Tibetan highlanders and to verify the hypothesis that high altitude dwelling increases vulnerability...

Spatial memory impairments in a prediabetic rat model

Diabetes is associated with an increased risk for brain disorders, namely cognitive impairments associated with hippocampal dysfunction underlying diabetic encephalopathy. However, the impact of a prediabetic state on cognitive function is unknown. Therefore, we now investigated whether spatial learning and memory deficits and the underlying hippocampal dysfunction were already present in a prediabetic animal model. Adult Wistar rats drinking high-sucrose (HSu) diet (35% sucrose solution during 9weeks) were compared to controls’ drinking water. HSu rats exhibited fasting normoglycemia accompanied by hyperinsulinemia and hypertriglyceridemia in the fed state, and insulin resistance with impaired glucose tolerance confirming them as a prediabetic rodent model. HSu rats displayed a poorer performance in hippocampal-dependent short- and long-term spatial memory performance, assessed with the modified Y-maze and Morris water maze tasks, respectively; this was accompanied by a reduction of insulin receptor-β density with normal levels of insulin receptor substrate-1 pSer636/639, and decreased hippocampal glucocorticoid receptor levels without changes of the plasma corticosterone levels. Importantly, HSu animals exhibited increased hippocampal levels of AMPA and NMDA receptor subunits GluA1 and GLUN1, respectively, whereas the levels of protein markers related to nerve terminals (synaptophysin) and oxidative stress/inflammation (HNE, RAGE, TNF-α) remained unaltered. These findings indicate that 9weeks of sucrose consumption resulted in a metabolic condition suggestive of a prediabetic state, which translated into short- and long-term spatial memory deficits accompanied by alterations in hippocampal glutamatergic neurotransmission and abnormal glucocorticoid signaling.

Renal Glucose Handling

OBJECTIVEIpragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function.RESEARCH DESIGN AND METHODSGlycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min–1 · 1.73 m−2), mild (eGFR2 ≥60 to <90), moderate (eGFR3 ≥30 to <60), or severe reduction in eGFR (eGFR4 ≤15 to <30).RESULTSIpragliflozin significantly increased urinary glucose excretion in each eGFR class (P < 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P < 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P < 0.0001 for both, r2 = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia.CONCLUSIONSIn T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.

Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker

BackgroundDiabetic cardiomyopathy (DCM) is defined as structural and functional changes in the myocardium due to metabolic and cellular abnormalities induced by diabetes mellitus (DM). The impact of prediabetic conditions on the cardiac tissue remains to be elucidated. The goal of this study was to elucidate whether cardiac dysfunction is already present in a state of prediabetes, in the presence of insulin resistance, and to unravel the underlying mechanisms, in a rat model without obesity and hypertension as confounding factors.MethodsTwo groups of 16-week-old Wistar rats were tested during a 9 week protocol: high sucrose (HSu) diet group (n = 7) – rats receiving 35% of sucrose in drinking water vs the vehicle control group (n = 7). The animal model was characterized in terms of body weight (BW) and the glycemic, insulinemic and lipidic profiles. The following parameters were assessed to evaluate possible early cardiac alterations and underlying mechanisms: blood pressure, heart rate, heart and left ventricle (LV) trophism indexes, as well as the serum and tissue protein and/or the mRNA expression of markers for fibrosis, hypertrophy, proliferation, apoptosis, angiogenesis, endothelial function, inflammation and oxidative stress.ResultsThe HSu-treated rats presented normal fasting plasma glucose (FPG) but impaired glucose tolerance (IGT), accompanied by hyperinsulinemia and insulin resistance (P < 0.01), confirming this rat model as prediabetic. Furthermore, although hypertriglyceridemia (P < 0.05) was observed, obesity and hypertension were absent. Regarding the impact of the HSu diet on the cardiac tissue, our results indicated that 9 weeks of treatment might be associated with initial cardiac changes, as suggested by the increased LV weight/BW ratio (P < 0.01) and a remarkable brain natriuretic peptide (BNP) mRNA overexpression (P < 0.01), together with a marked trend for an upregulation of other important mediators of fibrosis, hypertrophy, angiogenesis and endothelial lesions, as well as oxidative stress. The inflammatory and apoptotic markers measured were unchanged.ConclusionsThis animal model of prediabetes/insulin resistance could be an important tool to evaluate the early cardiac impact of dysmetabolism (hyperinsulinemia and impaired glucose tolerance with fasting normoglycemia), without confounding factors such as obesity and hypertension. Left ventricle hypertrophy is already present and brain natriuretic peptide seems to be the best early marker for this condition.

Sagittal Abdominal Diameter and Visceral Adiposity

In the context of increasing obesity prevalence, the relationship between large visceral adipose tissue (VAT) volumes and type 2 diabetes mellitus (T2DM) is unclear. In a clinical sample of severely obese women (mean body mass index [BMI], 46 kg/m(2)) with fasting normoglycemia (n = 40) or dysglycemia (impaired fasting glucose + diabetes; n = 20), we sought to determine the usefulness of anthropometric correlates of VAT and associations with dysglycemia. VAT volume was estimated using multi-slice computer tomography; anthropometric surrogates included sagittal abdominal diameter (SAD), waist circumference (WC) and BMI. Insulin sensitivity (Si), and beta-cell dysfunction, measured by insulin secretion (AIRg) and the disposition index (DI), were determined by frequently sampled intravenous glucose tolerance test. Compared to fasting normoglycemic women, individuals with dysglycemia had greater VAT (P < 0.001) and SAD (P = 0.04), but BMI, total adiposity and Si were similar. VAT was inversely associated with AIRg and DI after controlling for ancestry, Si, and total adiposity (standardized beta, -0.32 and -0.34, both P < 0.05). In addition, SAD (beta = 0.41, P = 0.02) was found to be a better estimate of VAT volume than WC (beta = 0.32, P = 0.08) after controlling for covariates. Receiver operating characteristic analysis showed that VAT volume, followed by SAD, outperformed WC and BMI in identifying dysglycemic participants. Increasing VAT is associated with beta-cell dysfunction and dysglycemia in very obese women. In the presence of severe obesity, SAD is a simple surrogate of VAT, and an indicator of glucose dysregulation.

Inhibition of dipeptidyl peptidase IV by sitagliptin increases GLUT4 expression in insulin‐sensitive tissues of SHR

The goal of the present study was to investigate whether the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which has been shown to exert both anti‐hyperglycemic and anti‐hypertensive actions, modulates GLUT4 expression in skeletal and cardiac muscles of SHR. To this end, male SHR at 5 and 20 weeks of age were treated with either sitagliptin (40 mg/kg twice daily) or vehicle for the period of ten days. Age‐matched Wistar Kyoto (WKY) rats were used as normotensive controls. Sitagliptin treatment inhibited the activity of DPPIV in the plasma of both young and adult SHR and also decreased the circulating levels of the enzyme. Sitagliptin only suppressed blood pressure rising in Y‐SHR. Levels of plasma insulin were not significantly different between the strains at young age. In contrast, adult SHR displayed enhanced plasma insulin concentration with fasting normoglycemia. Inhibition of DPPIV by sitagliptin restored plasma insulin levels of A‐SHR. GLUT4 in the plasma membrane (PM) was lower in Y‐SHR than in Y‐WKY in the heart, the slow‐twich oxidative soleus, the fast‐twich glycolytic EDL and the fast‐twich glycolytic‐oxidative gastrocnemius. DPPIV inhibition normalized PM GLUT4 in myocytes from Y‐SHR. Reduction of GLUT4 PM expression in the skeletal and cardiac myocytes was more pronounced in A‐SHR vs. A‐WKY than in Y‐SHR vs. YWKY. Inhibition of DPPIV by sitagliptin increased GLUT4 PM, total protein and GLUT4‐mRNA expression in the heart, soleus, EDL and gastrocnemius of treated‐A‐SHR to levels higher than those found in the A‐WKY. Collectively, our data demonstrate that DPPIV inhibition upregulates GLUT4 in skeletal and cardiac muscles of SHR.

Metabolic Imprinting by Maternal Protein Malnourishment Impairs Vagal Activity in Adult Rats

Protein restriction during lactation has been suggested to diminish parasympathetic activity, whereas sympathetic activity is enhanced in adult rats. The present study analyses whether dysfunction of the autonomic nervous system is involved in the impairment of insulin secretion from perinatally undernourished rats. Male neonates were reared by mothers fed a low- (4%) protein (LP group) or normal- (23%) protein diet (NP group). At 81 days of age, LP rats showed less body mass than NP rats (318 ± 4 g versus 370 ± 5 g) (P < 0.001). Fat tissue accumulation decreased in LP [0.8 ± 0.03 g/100 g body weight (BW)] compared to NP rats (1.1 ± 0.04 g/100 g BW) (P < 0.001). LP were glucose-intolerant as registered by the area under the curve of an i.v. glucose tolerance test (37 ± 3) compared to NP rats (29 ± 2) (P < 0.05); however, LP animals showed fasting normoglycaemia (LP, 5.0 ± 0.1; NP, 4.9 ± 0.03 mm) and hypoinsulinaemia (LP, 0.10 ± 0.02 ng/ml; NP, 0.17 ± 0.02 ng/ml). LP also showed glucose tissue uptake 60% higher than NP rats (P < 0.05). Vagus firing rate from LP was lower (7.1 ± 0.8 spikes/5 s) than that in NP rats (12.3 ± 0.7 spikes/5 s) (P < 0.001); however, there was no difference in sympathetic nervous activity. The cholinergic insulinotrophic effect was lower in pancreatic islets from LP (0.07 ± 0.01 ng/min/islet) than in NP rats (0.3 ± 0.06 ng/min/islet), whereas the levels of adrenaline-mediated inhibition of glucose-induced insulin release were similar. Perinatal protein restriction inhibited the activity of the vagus nerve, thus reducing the insulinotrophic effect of parasympathetic pathways on pancreatic β-cells, which inhibit insulin secretion.

Improvement in ß-cell function in patients with normal and hyperglycemia following Roux-en-Y gastric bypass surgery.

Glycemic disorders resolve following Roux-en-Y gastric bypass (RYGB) surgery, but early and longer-term mechanisms regarding effects on β-cell dysfunction as well as relationships with decreasing adiposity are not well understood. We evaluated longitudinal changes in peripheral insulin sensitivity (Si), the acute insulin response to glucose (AIRg), and the composite estimate of β-cell function, the disposition index (DI), over 24 mo via frequently sampled intravenous glucose tolerance testing in severely obese women who had fasting normoglycemia (n = 16) and hyperglycemia (n = 11) before RYGB surgery; homeostatic model assessment (HOMA-IR) estimated insulin resistance; air displacement plethysmography determined adipose tissue mass. At baseline, subjects with normoglycemia had adequate DI associated with elevated AIRg, but DI was markedly reduced in subjects with hyperglycemia. Within 1-6 mo post-RYGB, glycemic control was normalized in subjects with hyperglycemia related to reduced HOMA-IR (-54% at 1 mo, P < 0.005) and increased DI (23-fold at 6 mo vs. baseline, P < 0.05). Over 24 mo, DI improved in subjects with hyperglycemia (15-fold vs. baseline, P < 0.005) and also modestly in subjects with normoglycemia (58%, P < 0.05), due largely to increased Si. Decreasing adiposity correlated with longer-term HOMA-IR and Si values at 6 and 24 mo, respectively. In patients exhibiting fasting hyperglycemia before surgery, β-cell function improved early following RYGB, due largely to increases in insulin secretion. For both normoglycemic and hyperglycemic subjects, further improvement or stabilization of β-cell function over the 2 yr is due largely to improved Si associated with reduced adiposity.

Thiazide-type diuretics and beta-adrenergic blockers as first-line drug treatments for hypertension.

Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved. Response by Messerli et al p 2705 Before the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, “usual care.” For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines. The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, …

Adolescents at Risk for MODY3 Diabetes Prefer Genetic Testing Before Adulthood

Mutations in the hepatocyte nuclear factor (HNF)-1α gene cause an autosomally, dominantly inherited form of diabetes, maturity-onset diabetes of the young (MODY) type 3, which is characterized by poor insulin secretion in response to glucose together with good sensitivity to insulin and sulfonylurea medication and low renal threshold for glucose (1). The lifetime risk of diabetes may be as high as 95% for individuals carrying the most common Pro291fsinsC mutation. Glucose tolerance deteriorates in most cases during the pubertal years (2–5). However, because of fasting normoglycemia, clinical diagnosis is often delayed despite high postprandial glucose concentrations and an increased A1C value. Diabetes complications are common, and proliferative retinopathy has been detected already at diagnosis of diabetes in a 19-year-old carrier (6). On the other hand, while the incidence of diabetes among mutation carriers steeply increases in puberty, at least 20% remain nondiabetic until their 30s (2,4,5). Abnormal glucose tolerance in subjects at risk for MODY3 can be diagnosed with an oral glucose tolerance test. Urine glucose analysis after a large oral glucose load has also been advocated as a noninvasive screening tool in young children (7). Although an aberrant result from these tests has diagnostic value for diabetes and a certain predictive value in identification of probable carriers, they are not specific for MODY, and a normal result cannot exclude future risk. A genetic test seems to be warranted before adulthood, either to confirm carrier status in these prescreened subjects or in all at-risk subjects. A predictive test, whether a clinical or specific gene …

Protein restriction during lactation alters the autonomic nervous system control on glucose-induced insulin secretion in adult rats

Involvement of autonomic nervous system (ANS) neurotransmitters on insulin secretion in rats submitted to protein malnutrition during lactation was studied. During the first 2/3 of lactation, mothers received a 4% protein diet (LP). Control group received normal diet (23% protein) (NP). After protein restriction, mothers received normal diets. At 81 days rats were submitted to intravenous glucose tolerance tests (ivGTT). Plasma glucose and insulin concentration (PIC) were measured. Glucose-induced insulin secretion (GIIS) was tested in pancreatic islets. Fasting normoglycemia and hypoinsulinemia were observed in LP rats. Glucose intolerance and low PIC in LP group were detected during ivGTT. Acetylcholine (Ach) or blockage of α-adrenoceptors induced high PIC increment in LP rats; atropine or stimulation of α-adrenoceptors did not change PIC. Insulin secretion of LP rat islets showed low glucose and carbachol responses. Epinephrine-inhibited GIIS in both islet groups. Hypoinsulinemia observed in lactation-malnourished rats might be caused by alterations in GIIS regulation, including ANS modulation.