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OBJECTIVE--The barrier function of the glomerular filter has been studied for decades. Albuminuria reflects a malfunction of this barrier, and in animals dysfunctional endothelial nitric-oxide (NO) synthase results in albuminuria. We aimed to analyze the importance of NO for the glomerular barrier function in humans. RESEARCH DESIGN AND METHODS--To assess the effect of endothelial dysfunction on albuminuria, we measured the urine albumin-to-creatinine ratio (UACR) both before and after the blockade of NO synthases (NOSs) with systemic infusion of [N.sup.G]-monomethyl-L-arginine (L-NMMA) in two distinct study populations. In population A, 62 hypertensive patients with type 2 diabetes and, in population B, 22 patients with hypercholesterolemia but without hypertension or type 2 diabetes were examined. All subjects had normal renal function. RESULTS--There was a significant increase in the UACR in response to NOS inhibition with L-NMM.A in hypertensive patients with type 2 diabetes (study population A) and in patients with hypercholesterolemia (study population B). Linear regression analyses revealed that the change in mean arterial presssure in response to L-NMMA was not related to the increase in the UACR in response to L-NMMA in either population, even after adjusting for filtration fraction. CONCLUSIONS--NOS inhibition provokes albuminuria that is unrelated to changes in blood pressure. It is noteworthy that this finding was evident in patient groups prone to endothelial dysfunction and albuminuria. Thus, acute deterioration of endothelial function by reducing NO activity causes an increase in albuminuria., Albuminuria predicts renal disease progression and cardiovascular risk (1-3). There is increasing evidence for a continuous relation between albuminuria and cardiovascular risk, even at levels of albuminuria within the normal [...]

OBJECTIVE--Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied. RESEARCH DESIGN AND METHODS--We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after L-[[sup.15][N.sub.2]-guanidino]-arginine infusion, and use of precursor-product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic (~1,000-1,200 pmol/l) clamp. RESULTS--In type 2 diabetes, NOx FSR was reduced both under basal (19.3 ± 3.9% per day, vs. 22.9 ± 4.5% per day in control subjects) and hyperinsulinemic states (24.0 ± 5.6% per day, vs. 37.9 ± 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 ± 0.06 vs. 0.89 ± 0.34 tool per day; hyperinsulinemia, 0.35 ± 0.07 vs. 1.15 ± 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 ± 3.2% per day) and the ASR (0.03 ± 2 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 [+ or -] 2.9% per day and 0.25 ± 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 ± 0.05% vs. 0.65 ± 0.25%; hyperinsulinemia, 0.32 ± 0.06% vs. 1.03 ± 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA). CONCLUSIONS--In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism. Diabetes 59: 2152-2159, 2010, Nitric oxide (NO) is a key regulatory molecule with extensive metabolic, vascular, and cellular effects (1-6). The regulation of NO metabolism is particularly important in type 2 diabetes, because activation [...]

OBJECTIVE--To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS--This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM (≥ 2 abnormal values on a 100-g glucose tolerance test at ~28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM. RESULTS--Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013-18,939] vs. 30,670 [18,370-55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6-35.31) and multivariate (14.0 [4.1-47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ~28-week nonfasting glucose levels (r = -0.30, P < 0.001). CONCLUSIONS--First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy., Gestational diabetes mellitus (GDM) afflicts 4% of pregnancies in the U.S. and is associated with unfavorable perinatal outcomes (1). Although GDM is characterized by glucose intolerance, β-cell dysfunction, and insulin [...]

OBJECTIVE--Gestational diabetes is a risk factor for large-for-gestational-age (LGA) newborns, but many LGA babies are born to mothers with normal glucose tolerance. We aimed to clarify the association of maternal [...]

Type 2 diabetes is the most common form of diabetes in humans and results from a combination of genetic and acquired factors that impair β-cell function and tissue insulin sensitivity [...]

OBJECTIVE--This research investigated recent changes in the prevalence and management status of diabetes among Korean adults. RESEARCH DESIGN AND METHODS--The Korea National Health and Nutrition Examination Survey (KNHANES), a nationwide [...]

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the B-cell failure occurs much earlier and [...]

Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP [...]

Coronary artery disease is the predominant cause of death in diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators. Heat shock protein (Hsp) was upregulated in uncontrolled diabetic patients. Our previous studies demonstrated that glycated LDL stimulated the generation of PAI-1 from vascular endothelial cells. The present study examined the effect of glycated LDL on the expression of heat shock factor-1 (HSF1), a physiological transcription factor of Hsp, and the involvement of HSF-1 in glycated LDL-induced production of PAI-1 in cultured human umbilical vein endothelial cells (HUVECs) and coronary artery endothelial cells (HCAECs). Treatment with glycated LDL increased the expression of HSF1 and Hsp-70 compared with LDL in subconfluent HCAECs or HUVECs, and that was associated with an increase of PAI-1 expression. The transfection of HSF1 gene enhanced the expression of PAI-1 in endothelial cells. Small interference RNA against HSF1 prevented glycated LDL--induced upregulation of PAI-1 in HCAECs or HUVECs. Glycated LDL increased the binding of a nuclear protein to the PAI-1 promoter. The nuclear protein--DNA complex was supershifted by HSFI antibody. The presence of an antioxidant, butylated hydroxytulene, during the glycation of LDL prevented glycated LDL--induced increases of the expression of HSF1 or PAI-1 in endothelial cells. The results suggest that HSF-1 is involved in glycated LDL-induced upregulation of PAI-1 in subconfluent vascular endothelial cells through the binding of HSF1 to PAI-1 promoter. Glyco-oxidation may contribute to glycated LDL--induced expression of HSF1 and PAI-1 in endothelial cells., The incidence of diabetes in North America has rapidly increased during the last three decades, and the trend is expected to continue (1). The most common cause of death in [...]

OBJECTIVE--To examine the outcome of neuropathic foot ulcers and to seek associations between healing and features of the ulcers at baseline. RESEARCH DESIGN AND METHODS--Data were collected prospectively during the [...]

OBJECTIVE--Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or [...]

Insulin secretion from the 2,000-3,000 β-cells in an islet is a highly synchronized activity with discharge of insulin in coordinate secretory bursts at approximately 4-min intervals. Insulin secretion progressively declines in type 2 diabetes and following islet transplantation. Both are characterized by the presence of islet amyloid derived from islet amyloid polypeptide (IAPP). In the present studies, we examined the action of extracellular human IAPP (h-IAPP) on morphology and function of human islets. Because oligomers of h-IAPP are known to cause membrane disruption, we questioned if application of h-IAPP oligomers to human islets would lead to disruption of islet architecture (specifically cell-to-cell adherence) and a decrease in coordinate function (e.g., increased entropy of insulin secretion and diminished coordinate secretory bursts). Both hypotheses are affirmed, leading to a novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers., In health, insulin secretion is predominantly derived from discrete insulin secretory bursts occurring at ~4- to 6-min intervals (1-4). Increased insulin secretion in response to hyperglycemia is accomplished by amplification [...]

Pancreatic islets were isolated from 16 nondiabetic organ donors and, after culture for ~2 days in 5 mmol/l glucose, were perifused to characterize nutrient-induced insulin secretion in human islets. Stepwise increases from 0 to 30 mmol/l glucose (eight 30-min steps) evoked concentration-dependent insulin secretion with a threshold at 3-4 mmol/l glucose, [K.sub.m] at 6.5 mmol/l glucose, and [V.sub.max] at 15 mmol/l glucose. An increase from 1 to 15 mmol/l glucose induced biphasic insulin secretion with a prominent first phase (peak increase of ~18-fold) and a sustained, flat second phase (~10-fold increase), which were both potentiated by forskolin. The central role of ATP-sensitive [K.sup.+] channels in the response to glucose was established by abrogation of insulin secretion by diazoxide and reversible restoration by tolbutamide. Depolarization with tolbutamide or KCl (plus diazoxide) triggered rapid insulin secretion in 1 mmol/l glucose. Subsequent application of 15 mmol/l glucose further increased insulin secretion, showing that the amplifying pathway is operative. In control medium, glutamine alone was ineffective, but its combination with leucine or nonmetabolized 2-amino-bicyclo [2,2,1]-heptane-2-carboxylic acid (BCH) evoked rapid insulin secretion. The effect of BCH was larger in low glucose than in high glucose. In contrast, the insulin secretion response to arginine or a mixture of four amino acids was potentiated by glucose or tolbutamide. Palmitate slightly augmented insulin secretion only at the supraphysiological palmitate-to-albumin ratio of 5. Inosine and membrane-permeant analogs of pyruvate, glutamate, or succinate increased insulin secretion in 3 and 10 mmol/l glucose, whereas lactate and pyruvate had no effect. In conclusion, nutrient-induced insulin secretion in normal human islets is larger than often reported. Its characteristics are globally similar to those of insulin secretion by rodent islets, with both triggering and amplifying pathways. The pattern of the biphasic response to glucose is superimposable on that in mouse islets, but the concentration-response curve is shifted to the left, and various nutrients, in particular amino acids, influence insulin secretion within the physiological range of glucose concentrations., Glucose homeostasis requires precise control of insulin secretion by pancreatic β-cells. This control is primarily ensured by glucose itself, but it also involves other nutrients and numerous neural and hormonal [...]

OBJECTIVE--The study was to determine whether being the macrosomic offspring of a mother without detected glucose intolerance during pregnancy has an impact on lipid profile, glucose homeostasis, and blood pressure [...]

The objective of this study was to establish the baseline retinal hemodynamic characteristics of stratified groups of diabetic patients at increasing risk for the development of diabetic macular edema (DME). Group 1 had 50 control subjects, group 2 had 56 diabetic patients without clinically visible retinopathy, group 3 had 54 diabetic patients with microaneurysms and/or hard exudates within two disc diameters of the fovea in the absence of clinically manifest DME, and group 4 had 40 patients with clinically manifest DME. Retinal hemodynamics (diameter, velocity, maximum-to-minimum velocity ratio, and flow) were assessed. Intraocular pressure, blood pressure, and relevant systemic markers of diabetes control and complications were also undertaken. The maximum-to-minimum velocity ratio was elevated with increasing risk of clinically significant DME (P < 0.0001). No significant differences were found between the groups with respect to diameter, velocity, or flow. The maximum-to-minimum velocity ratio was correlated to age, duration of diabetes, blood pressure, pulse rate, intraocular pressure, and serum potassium levels. In conclusion, the maximum-to-minimum velocity ratio was significantly increased with increasing risk of development of DME. Retinal arteriolar hemodynamics were positively correlated to age, duration of diabetes, and blood pressure. These findings suggest a reduction in the compliance (i.e., an increase of vascular rigidity) of the arteriolar circulation with increasing risk of DME., Diabetic retinopathy is a leading cause of visual impairment in the world, including North America (1). Due to the increasing prevalence of diabetes, the financial, societal, and personal burden of [...]

OBJECTIVE--The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted [...]

OBJECTIVE--To analyze the impact of age at onset on the development of end-stage renal disease (ESRD) due to diabetic nephropathy in a nationwide population-based cohort with childhood-onset type 1 diabetes. [...]

Several lines of evidence, including familial aggregation, suggest that allelic variation contributes to risk of diabetic nephropathy. To assess the evidence for specific susceptibility genes, we used the transmission/disequilibrium test (TDT) to analyze 115 candidate genes for linkage and association with diabetic nephropathy. A comprehensive survey of this sort has not been undertaken before. Single nucleotide polymorphisms and simple tandem repeat polymorphisms located within 10 kb of the candidate genes were genotyped in a total of 72 type 1 diabetic families of European descent. All families had at least one offspring with diabetes and end-stage renal disease or proteinuria. As a consequence of the large number of statistical tests and modest P values, findings for some genes may be false-positives. Furthermore, the small sample size resulted in limited power, so the effects of some tested genes may not be detectable, even if they contribute to susceptibility. Nevertheless, nominally significant TDT results (P < 0.05) were obtained with polymorphisms in 20 genes, including 12 that have not been studied previously: aquaporin 1; B-cell leukemia/lymphoma 2 (bcl-2) proto-oncogene; catalase; glutathione peroxidase 1; IGF1; laminin alpha 4; laminin, gamma 1; SMAD, mothers against DPP homolog 3; transforming growth factor, beta receptor II; transforming growth factor, beta receptor Ill; tissue inhibitor of metalloproteinase 3; and upstream transcription factor 1. In addition, our results provide modest support for a number of candidate genes previously studied by others., Diabetic nephropathy is the most serious long-term complication of diabetes, accounting for ~40% of new cases of end-stage renal disease (ESRD) in the U.S. (1). Two lines of evidence suggest [...]

Different degrees of β-cell failure and apoptosis are present in type 1 and type 2 diabetes. It has been recently suggested that high glucose-induced β-cell apoptosis in type 2 diabetes shares a final common pathway with type 1 diabetes, involving interleukin-1β (IL-1β) production by β-cells, nuclear factor-κB (NF-κB) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1β expression and consequent activation of NF-κB-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1β Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1β nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1β and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released >50-fold more IL-1β than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-κB-dependent genes IκB-α and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1β but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1β, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1β production or NF-κB activation in human islets. This makes it unlikely that locally produced IL-1β is an important mediator of glucotoxicity to human islets and argues against the IL-1β-NF-κB-Fas pathway as a common mediator for β-cell death in type 1 and type 2 diabetes., Chronic β-cell exposure to hyperglycemia and/or elevated free fatty acids may lead to dysfunction and death of β-cells in type 2 diabetes, a phenomenon denominated by glucotoxicity or glucolipotoxicity (1-3). [...]

Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means ± SE from 13.5 ± 0.62 to 9.8 ± 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P < 0.008) during the insulin suppression test and by 21% (P < 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR., In insulin-resistant individuals, glucose homeostasis can be maintained if the defect in insulin action is adequately compensated for by an increase in insulin concentration. This is achieved by a shift [...]

Islet amyloid deposition in type 2 diabetes is associated with reduced [beta]-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve [beta]-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce [beta]-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced [beta]-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5 mg x [kg.sup.-1] x [day.sup.-1], n = 19), metformin (1 g x [kg.sup.-1] x [day.sup.-1], n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, [beta]-cell mass, and insulin release were determined. Islet amyloid prevalence (44 [+ or -] 8, 13 [+ or -] 4, and 11 [+ or -] 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 [+ or -] 3.0, 0.22 [+ or -] 0.11, and 0.10 [+ or -] 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 [+ or -] 857, 621 [+ or -] 256, and 14 [+ or -] 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 [+ or -] 7.0, 16.6 [+ or -] 3.6, and 12.2 [+ or -] 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in [beta]-cell mass (percent [beta]-cell mass/islet mass) was ameliorated in both rosiglitazone- and metformin-treated animals (57.9 [+ or -] 3.1, 64.7 [+ or -] 1.4, and 66.1 [+ or -] 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect [beta]-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of [beta]-cell mass and function in type 2 diabetes., Type 2 diabetes is characterized by insulin resistance and islet [beta]-cell secretory dysfunction. In addition, several studies (1-3) have shown that reduced [beta]-cell mass is a feature of the disease. [...]

OBJECTIVE--By age 5 years, offspring of diabetic mothers (ODMs) are heavier and have altered glucose metabolism compared with offspring of mothers without diabetes (non-DMs). This study evaluates the growth pattern [...]

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy., Diabetes is a chronic metabolic syndrome caused by insulin deficiency. There are ~200 million diabetic individuals in the world, with only about half being diagnosed, and these numbers are expected [...]

Free fatty acids (FFAs) and glycerol oscillate in plasma. This study examined intrinsic lipolytic oscillations within adipocytes. Rat adipocytes were perifused with Krebs-Ringer bicarbonate buffer: 1) ± 2 mmol/l glucose; 2) +1 µmol/l isoproterenol ± 2 mmol/l glucose; 3) + increasing oleate; and 4) + increasing percent BSA. At 2 mmol/l glucose, there were 9 ± 1 glycerol, FFAs, and lactate pulses per hour with a pulse duration of 5 ± 1 mill. Lipolytic stimulation caused a 50-80% increase in the amplitude of lipolytic oscillations. Removal of glucose caused a 40-70% decrease in the amplitude of lipolytic oscillations and disturbed the pulsatility. Exogenous FFAs suppressed lipolysis and oscillatory amplitude, possibly because of increased cytosolic longchain coenzyme A (LC-CoA). Increasing percent BSA increased stimulated lipolysis and oscillatory amplitude, possibly because of decreased intracellular LC-CoA. These data show, for the first time, intrinsic lipolytic oscillations, which are glucose dependent and modulated by FFAs. We hypothesize that lipolytic oscillations are driven by oscillatory glucose metabolism, which leads to oscillatory relief of LC-CoA inhibition of triglyceride lipase(s). The results contribute to the understanding of physiological and biochemical regulators of lipolysis, such as glucose and FFAs. Lipolytic oscillations may be beneficial in the delivery of FFAs to liver, pancreas, and other tissues., Abnormal fat metabolism plays an important role in the pathogenesis of obesity-related type 2 diabetes (1-4), and elevated plasma free fatty acid (FFA) concentrations are associated with peripheral and hepatic [...]

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of [sup.125]I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and mieroalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER., Deckert et al. (1) suggested some years ago an interesting view to understanding the pathogenesis of albuminuria in diabetes, which has been usually cited as the Steno hypothesis and implies [...]

Physiologically, insulin secretion is subject to a dual, hierarchal control by triggering and amplifying pathways. By closing ATP-sensitive [K.sup.+] channels (KATP channels) in the plasma membrane, glucose and other metabolized nutrients depolarize β-cells, stimulate [Ca.sup.2+] inflox, and increase the cytosolic concentration of free [Ca.sup.2+] ([[[Ca.sup.2+]].sub.i]), which constitutes the indispensable triggering signal to induce exocytosis of insulin granules. The increase in β-cell metabolism also generates amplifying signals that augment the efficacy of [Ca.sub.2+] on the exocytotic machinery. Stimulatory hormones and neurotransmitters modestly increase the triggering signal and strongly activate amplifying pathways biochemically distinct from that set into operation by nutrients. Many drugs can increase insulin secretion in vitro, but only few have a therapeutic potential. This review identifies six major pathways or sites of stimulus-secretion coupling that could be aimed by potential insulin-secreting drugs and describes several strategies to reach these targets. It also discusses whether these perspectives are realistic or theoretical only. These six possible β-cell targets are 1) stimulation of metabolism, 2) increase of [[[Ca.sup.2+]].sub.i] by closure of K+ATP channels, 3) increase of [[[Ca.sup.2+]].sub.i] by other means, 4) stimulation of amplifying pathways, 5) action on membrane receptors, and 6) action on nuclear receptors. The theoretical risk of inappropriate insulin secretion and, hence, of hypoglycemia linked to these different approaches is also envisaged., Optimal treatment of type 2 diabetes is difficult because of the complex pathogenesis of the disease (1,2). Pharmacological agents improving the action of insulin on its target tissues and agents [...]

A decade ago we proposed that environmental factors operating in early life lead to type 1 diabetes, outlining the evidence and the implications if the hypothesis was true (1). Today [...]

OBJECTIVE--This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. [...]

OBJECTIVE--Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence [...]

Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration. Indeed, we found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also found to be augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated β-cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting expansion of precursor cells during pancreas growth., Activins, members of the transforming growth factor (TGF)-β superfamily, are important in the differentiation of several distinct types of cells and govern embryonic axial patterning and function of foregut-derived organs [...]

OBJECTIVE--To determine if insulin sensitivity is altered in prepubertal offspring exposed to a diabetic intrauterine environment. RESEARCH DESIGN AND METHODS--Fifteen control children, 17 offspring of type I diabetic women, and [...]

The atrial natriuretic peptide gene (PND) is a candidate gene for diabetic nephropathy. We systematically analyzed five nonsynonymous PND polymorphisms and tested the association of genotype and haplotype distributions with diabetic nephropathy in a cross-sectional study and a 6-year follow-up study (489 and 301 type 1 diabetic patients, respectively). For this purpose, a new maximum-likelihood method dealing with haplotype-based association analysis for survival data was developed. None of the genotypes or haplotypes were associated with the disease in the case-control study. In the follow-up study, C708T and T2238C showed a weak association with disease progression, but T2238C was strongly associated with progression in poorly controlled subjects (mean Hb[A.sub.1e] during follow-up was more than the median value [8.5%]; log-rank [TC or CC versus TT], P = 0.007; adjusted hazard ratio, TC or CC versus TT, 2.28, 95% CI 1.10-4.74; P = 0.027). The raw effect of the 2238C allele (hazard risk ratio 1.93, 95% CI 1.15-3.24; P = 0.012) was further confirmed by the haplotype analysis, suggesting that the 2238C allele of PND may affect the course of nephropathy in inadequately controlled type 1 diabetic patients., Diabetic nephropathy results from the interaction of genetic factors with chronic hyperglycemia. Atrial natriuretic peptide (ANP) may affect the course of diabetic nephropathy by inducing afferent arteriolar dilatation and efferent [...]

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic β-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop--the so-called 'adipo-insular axis.' Multiple signal transduction pathways are involved in leptin signaling in pancreatic β-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic β-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing 'leptin resistance.' This leptin resistance at the level of the pancreatic β-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients. Diabetes 53 (Suppl. 1): S152-S158, 2004, The Ob gene was identified through positional cloning in 1994, and it was demonstrated that mutations in the ob gene of ob/ob mice prevent synthesis of a functional leptin protein [...]

OBJECTIVE--To evaluate the safety and efficacy of first metatarsophalangeal joint arthroplasty compared with standard, nonsurgical management of wounds at the plantar hallux interphalangeal joint in patients with diabetes. RESEARCH DESIGN [...]

OBJECTIVE--This study was designed to evaluate the histopathology of neuropathic ulcers and whether pressure relief could change such histological patterns. RESEARCH DESIGN AND METHODS--We compared neuropathic plantar ulcers tissue excised [...]

OBJECTIVE--To study the relationships between the PC-1 K121Q variant and diabetic nephropathy (DN) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--A total of 125 patients with type 2 [...]

OBJECTIVE -- This study examines the relationship of glucose intolerance during pregnancy to birth weight among black and white participants of the Pregnancy, Infection, and Nutrition Study RESEARCH DESIGN AND [...]

Differentiation and maturation of porcine neonatal pancreatic cell clusters (NPCCs) microencapsulated in barium alginate were assessed after transplantation into immunocompetent mice. Microencapsulated NPCCs were transplanted into the peritoneal cavity of streptozocin-induced diabetic B6AF1 mice (n = 32). The microcapsules were removed at 2, 6, and 20 weeks and examined for cellular overgrowth, insulin content, and insulin secretory responses to glucose and glucose with theophylline. The differentiation, maturation, and proliferation of the β-cells in the NPCCs were assessed by immunohistochemistry. Blood glucose levels were normalized in 81% of the animals that received a transplant and remained normal until termination of the experiments at 20 weeks. Hyperglycemic blood glucose levels after explantation of the capsules confirmed the function of the encapsulated NPCCs. Insulin content of the encapsulated NPCCs was increased 10-fold at 20 weeks after transplantation compared with pretransplantation levels. A 3.2-fold increase of the ratio of the β-cell area to the total cellular area was observed at 20 weeks, demonstrating the maturation of NPCCs into β-cells. In conclusion, NPCCs encapsulated with simple barium alginate can differentiate into β-cells and reverse high blood glucose levels in immunocompetent mice Without immunosuppression for >20 weeks., As a result of recent progress (1), there is increased interest in islet transplantation as a potential therapy for type 1 diabetes. However, two major barriers must be overcome before [...]

Autoantibodies against CD38 (adenosine-5'-diphosphate[ADP]-ribosyl cyclase/cyclic ADP-ribose hydrolase) have been described in 10-12% of patients with type 2 diabetes. In human islets, anti-CD38 autoantibodies (CD38Abs) acutely stimulate insulin release (IR) and increase the cytosolic calcium concentration ([[Ca.sup.2+].sub.i]). Whether CD38Abs affect human islet cell function and survival upon prolonged in vitro exposure is not known. We cultured human islets for up to 7 days in the presence of sera from 10 patients with type 2 diabetes that had neither CD38Ab- nor [[Ca.sup.2+].sub.i]-mobilizing activity (-/-), sera front 6 patients with type 2 diabetes that was CD38Ab-positive and had [[Ca2+].sub.i]mobilizing activity (+/+), or no sera (control). At baseline, +/+ sera caused a significant (P < 0.002) acute stimulation of IR (IR at 3.3 mmol/l glucose was 45 ± 19, 84 ± 24, and 34 ± 12 µU/ml in control, +/+, and -/sera, respectively; the corresponding IR at 16.7 mmol/l glucose was 72 ± 25, 204 ± 56, and 80 ± 32 µU/ml). At 3 days, IR at 3.3 mmol/l glucose was 42 ± 18, 27 ± 11, and 43 ± 24 µU/ml (P = 0.0003) for control, +/+, and -/- sere, respectively, whereas at 16.7 mmol/1 glucose, it was 95 ± 76, 45 ± 35, and 76 ± 42 µU/ml, respectively. After 7 days of exposure, the corresponding IR at 3.3 mmol/1 glucose was 40 ± 11, 28 ± 12, and 35 ± 15 µU/ml, respectively, whereas at 16.7 mmol/l glucose it was 79 ± 39, 39 ± 17, and 62 ± 39 µU/ml. At both 3 and 7 days, IR still increased when switching from 3.3 to 16.7 mmol/1 glucose (P < 0.0003), and incubation with +/+ sera induced a significant decrease in the insulin response (P < 0.002). At 7 days, the number of dead cells (as evaluated by an enzyme-linked immunosorbent assay technique) differed significantly between control (1.2 ± 0.3 OD units) cells, islets exposed to -/- sera (1.4 ± 0.1), and islets coincubated with +/+ sera (1.9 ± 0.4, P < 0.01). We conclude that prolonged exposure of human islets to sera positive for the presence of CD38Abs with [[Ca.sup.2+].sub.i]-mobilizing activity impairs Β-cell function and viability in cultured human pancreatic islets. Diabetes 51 (Suppl. 3):S474-S477, 2002, CD38 (adenosine-5'-diphosphale[ADP]-ribosyl cyclase/cyclic ADP-ribose hydrolase) is a surface and cytosolic enzyme that catalyzes the interconversion of NAD + and cyclic ADP-ribose (1,2). CD38 is expressed on the surface of monocytes, [...]

β-Cells possess inherent mechanisms to adapt to overnutrition and the prevailing concentrations of glucose, fatty acids, and other fuels to maintain glucose homeostasis. However, this is balanced by potentially harmful actions of the same nutrients. Both glucose and fatty acids may cause good/adaptive or evil/toxic actions on the β-cell, depending on their concentrations and the time during which they are elevated. Chronic high glucose dramatically influences β-cell lipid metabolism via substrate availability, changes in the activity and expression of enzymes of glucose and lipid metabolism, and modifications in the expression level of key transcription factors. We discuss here the emerging view that β-cell 'glucotoxicity' is in part indirectly caused by 'lipotoxicity,' and that β-cell abnormalities will become particularly apparent when both glucose and circulating fatty acids are high. We support the concept that elevated glucose and fatty acids synergize in causing toxicity in islets and other organs, a process that may be instrumental in the pleiotropic defects associated with the metabolic syndrome and type 1 and type 2 diabetes. The mechanisms by which hyperglycemia and hyperlipidemia alter insulin secretion are discussed and a model of β-cell 'glucolipotoxicity' that implicates alterations in β-cell malonyl-CoA concentrations; peroxisome proliferator--activated receptor-α and -γ and sterol regulatory element binding protein-1c expression; and lipid partitioning is proposed., Type 2 diabetes is considered to be in most cases a polygenic disease with a strong involvement of environmental factors, such as diet and exercise (1). Glucose intolerance in association [...]

OBJECTIVE -- Diabetic maculopathy (DMa) is the most prevalent sight-threatening type of retinopathy in type 2 diabetes and a leading cause of visual loss in the western world. The disease [...]

OBJECTIVE -- Patients with diabetes who manifest proteinuria are at increased risk for cardiovascular events. Some studies suggest that proteinuria exerts its cardiovascular effects at least partly through a positive [...]

OBJECTIVE--This article tests the hypothesis that women with impaired glucose tolerance (IGT) have the same pregnancy outcomes as those of their counterparts with normal glucose tolerance. RESEARCH DESIGN AND METHODS--From [...]

OBJECTIVE -- Differences in risk of erectile dysfunction (ED) by characteristics of diabetes among older men are not well understood. We examined the association of type and duration of diabetes [...]

OBJECTIVE -- Impaired glucose tolerance (IGT) is believed to be a prediabetic phase that precedes the development of type 2 diabetes. In elderly subjects, IGT and diabetes are both independently [...]