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Aims/Introduction: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c − predicted HbA1c derived from the continuous glucose monitoring [CGM]). Materials and Methods: We conducted a cross‐sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed. Results: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R2 = 0.44). Conclusions: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims: The relationship between diabetic microvascular complications and the incidence of two types of heart failure—heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] < 40%) and non‐HFrEF (LVEF ≥ 40%)—in patients without prior heart failure has not been clarified. We herein examined the association between diabetic microvascular complications and HFrEF or non‐HFrEF in patients with type 2 diabetes mellitus (T2DM) without prior heart failure. Methods and results: In this retrospective cohort study, we assessed the relationship between the presence of diabetic microvascular complications or severity of diabetic retinopathy (no apparent, non‐proliferative and proliferative retinopathy) and nephropathy (normoalbuminuria, microalbuminuria, and macroalbuminuria) at baseline, with the primary outcome of first heart failure hospitalization classified as HFrEF or non‐HFrEF in patients with type 2 diabetes mellitus without prior heart failure. Among 568 patients (69.2% males, mean age 66.2 ± 9.6 years), 70 experienced heart failure hospitalization (HFrEF: 24 and non‐HFrEF: 46). Non‐HFrEF hospitalization but not HFrEF hospitalization was significantly associated with the presence of diabetic microvascular complications. The incidence of non‐HFrEF hospitalization was significantly higher in the proliferative retinopathy group than that in the no apparent retinopathy group (adjusted hazard ratio [HR] 2.96, 95% confidence interval [CI]: 1.09–6.83, P = 0.035) and in those with macroalbuminuria than in those with normoalbuminuria (adjusted HR 4.23, 95% CI: 2.24–7.85, P < 0.001) even after adjustment for age and sex. When non‐HFrEF was classified into heart failure with mildly reduced ejection fraction (HFmrEF) (40% ≤ LVEF < 50%) and heart failure with preserved ejection fraction (HFpEF) (50% ≤ LVEF), HFmrEF and HFpEF hospitalizations were also found to be associated with the progression of retinopathy and nephropathy. Conclusions: In patients with T2DM without prior heart failure, non‐HFrEF hospitalization was more closely associated with the progression of diabetic microangiopathy than HFrEF. The development of non‐HFrEF may be mediated through a mechanism similar to that of microvascular complications in these patients. [ABSTRACT FROM AUTHOR]

Increased expression and activity of the intracellular glucocorticoid-reactivating enzyme 11[beta]-hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) contribute to dysfunction of adipose tissue. Although the pathophysiological role of 11[beta]-HSD1 in mature adipocytes has long been investigated, its potential role in preadipocytes still remains obscure. The present study demonstrates that the expression of 11[beta]-HSD1 in preadipocyte-rich stromal vascular fraction (SVF) cells in fat depots from ob/ob and diet-induced obese mice was markedly elevated compared with lean control. In 3T3-L1 preadipocytes, the level of mRNA and reductase activity of 11[beta]-HSD1 was augmented by TNF-[alpha], IL-1[beta], and LPS, with a concomitant increase in inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), or IL-6 secretion. Pharmacological inhibition of 11[beta]-HSD1 and RNA interference against 11[beta]-HSD1 reduced the mRNA and protein levels of iNOS, MCP-1, and IL-6. In contrast, overexpression of 11[beta]-HSD1 further augmented TNF-[alpha]-induced iNOS, IL-6, and MCP-1 expression. Moreover, 11[beta]-HSD1 inhibitors attenuated TNF-[alpha]-induced phosphorylation of NF-[kappa]B p65 and p38-, JNK-, and ERK1/2-MAPK. Collectively, the present study provides novel evidence that inflammatory stimuli-induced 11[beta]-HSD1 in activated preadipocytes intensifies NF-[kappa]B and MAPK signaling pathways and results in further induction of proinflammatory molecules. Not limited to 3T3-L1 preadipocytes, we also demonstrated that the notion was reproducible in the primary SVF cells from obese mice. These findings highlight an unexpected, proinflammatory role of reamplified glucocorticoids within preadipocytes in obese adipose tissue. 11[beta]-hydroxysteroid dehydrogenase type 1; preadipocyte; nuclear factor-[kappa]B; mitogen-activated protein kinase; adipose inflammation doi: 10.1152/ajpendo.00320.2009.

Ghrelin is a stomach-derived peptide that has growth hormone-stimulating and orexigenic activities. Although there have been several reports of ghrelinoma cases, only a few cases have elevated circulating ghrelin levels, hampering the investigation of pathophysiological features of ghrelinoma and chronic effects of ghrelin excess. Furthermore, standard transgenic technique has resulted in desacyl ghrelin production only because of the limited tissue expression of ghrelin O-acyltransferase, which mediates acylation of ghrelin. Accordingly, we attempted to create ghrelin promoter SV40 T-antigen transgenic (GP-Tag Tg) mice, in which ghrelin-producing cells continued to proliferate and finally developed into ghrelinoma. Adult GP-Tag Tg mice showed elevated plasma ghrelin levels with preserved physiological regulation. Adult GP-Tag Tg mice with increased plasma ghrelin levels exhibited elevated IGF-I levels despite poor nutrition. Although basal growth hormone levels were not changed, those after growth hormone-releasing hormone injection tended to be higher. These results indicate that chronic elevation of ghrelin activates GH-IGF-I axis. In addition, GP-Tag Tg mice demonstrated glucose intolerance. Insulin secretion by glucose tolerance tests was significantly attenuated in GP-Tag Tg, whereas insulin sensitivity determined by insulin tolerance tests was preserved, indicating that chronic elevation of ghrelin suppresses insulin secretion and leads to glucose intorelance. Thus, we successfully generated a Tg model of ghrelinoma, which is a good tool to investigate chronic effects of ghrelin excess. Moreover, their characteristic features could be a hint on ghrelinoma. ghrelin; glucose metabolism

Obesity is characterized by markedly decreased ghrelin and growth hormone (GH) secretion. Ghrelin is a GH-stimulating, stomach-derived peptide that also has orexigenic action. Ghrelin supplement may restore decreased GH secretion in obesity, but it may worsen obesity by its orexigenic action. To reveal effects of ghrelin administration on obese animals, we first examined acute GH and orexigenic responses to ghrelin in three different obese and/or diabetic mouse models: db/db mice, mice on a high-fat diet (HFD mice), and Akita mice for comparison. GH responses to ghrelin were significantly suppressed in db/db, HFD, and Akita mice. Food intake of db/db and Akita mice were basally higher, and further stimulation of food intake by ghrelin was suppressed. Pituitary GH secretagogue receptor mRNA levels in db/db and HFD mice were significantly decreased, which may partly contribute to decreased GH response to ghrelin in these mice. In Akita mice for comparison, decreased hypothalamic GH-releasing hormone (GHRH) mRNA levels may be responsible for decreased GH response, since maximum GH response to ghrelin needs GHRH. When ghrelin was injected into HFD mice with GHRH coadministrated, GH responses to ghrelin were significantly emphasized. HFD mice injected with low-dose ghrelin and GHRH for 10 days did not show weight gain. These results indicate that low-dose ghrelin and GHRH treatment may restore decreased GH secretion in obesity without worsening obesity. growth hormone secretagogue receptor; obesity; diabetes

A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR([alpha], -[gamma] and -[delta]) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11[beta]-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11[beta]-HSD1 preferentially in adipose tissue of db/db mice (-47%, P < 0.05), concomitant with a significant increase in plasma adiponectin level (+37%, P < 0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (-34%, P < 0.01) and enzyme activity (-32%, P < 0.01) of 11[3-HSD1, whereas the treatment substantially augmented the expression (+71%, P < 0.01) and secretion (+27%, P < 0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11[beta]-HSD1 by siRNA confirmed that 11[beta]-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11[beta]-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11[beta]-HSD 1 and adiponectin in murine adipocytes, both of which may contribute to metabolicallybeneficial effects by bezafibrate. metabolic syndrome; adiponectin

Skeletal muscle expresses two catalytic subunits, [alpha]1 and [alpha]2, of the 5'-AMP-activated protein kinase (AMPK), which has been implicated in contraction-stimulated glucose transport and fatty acid oxidation. Muscle contraction activates the [alpha]2-containing AMPK complex (AMPK[alpha]2), but this activation may occur with or without activation of the [alpha]1-containing AMPK complex (AMPK[alpha]1), suggesting that AMPK[alpha]2 is the major isoform responsible for contraction-induced metabolic events in skeletal muscle. We report for the first time that AMPK[alpha]1, but not AMPK[alpha]2, can be activated in contracting skeletal muscle. Rat epitrochlearis muscles were isolated and incubated in Krebs-Ringer bicarbonate buffer containing pyruvate. In muscles stimulated to contract at a frequency of 1 and 2 Hz during the last 2 min of incubation, AMPK[alpha]1 activity increased twofold and AMPK[alpha]2 activity remained unchanged. Muscle stimulation did not change the muscle AMP concentration or the AMP-to-ATP ratio. AMPK activation was associated with increased phosphorylation of [Thr.sup.172] of the [alpha]-subunit, the primary activation site. Muscle stimulation increased the phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK, and the rate of 3-O-methyl-D-glucose transport. In contrast, increasing the frequency ([greater than or equal to] 5 Hz) or duration ([greater than or equal to] 5 min) of contraction activated AMPK[alpha]1 and AMPK[alpha]2 and increased AMP concentration and the AMP/ATP ratio. These results suggest that 1) AMPK[alpha]1 is the predominant isoform activated by AMP-independent phosphorylation in low-intensity contracting muscle, 2) AMPK[alpha]2 is activated by an AMP-dependent mechanism in high-intensity contracting muscle, and 3) activation of each isoform enhances glucose transport and ACC phosphorylation in skeletal muscle. exercise; twitch; glucose transport; acetyl-coenzyme A carboxylase; [beta]-oxidation

Recent studies have suggested that 5'AMP-activated protein kinase (AMPK) is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation, which leads to insulin-independent glucose transport in skeletal muscle. In the present study, we hypothesized that acute oxidative stress increases the rate of glucose transport via an AMPK-mediated mechanism. When rat epitrochlearis muscles were isolated and incubated in vitro in Krebs buffer containing the oxidative agent [H.sub.2][O.sub.2], AMPK[alpha]1 activity increased in a time- and dose-dependent manner, whereas AMPK[alpha]2 activity remained unchanged. The activation of AMPK[alpha]1 was associated with phosphorylation of AMPK [Thr.sup.172], suggesting that an upstream kinase is involved in the activation process. [H.sub.2][O.sub.2]-induced AMPK[alpha]1 activation was blocked in the presence of the antioxidant N-acetyl-L-cysteine (NAC), and [H.sub.2][O.sub.2] significantly increased the ratio of oxidized glutathione to glutathione (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. [H.sub.2][O.sub.2] did not cause an increase in the conventional parameters of AMPK activation, such as AMP and AMP/ATP. [H.sub.2][O.sub.2] increased 3-O-methyl-D-glucose transport, and this increase was partially, but significantly, blocked in the presence of NAC. Results were similar when the muscles were incubated in a superoxide-generating system using hypoxanthine and xanthine oxidase. Taken together, our data suggest that acute oxidative stress activates AMPK[alpha]1 in skeletal muscle via an AMP-independent mechanism and leads to an increase in the rate of glucose transport, at least in part, via an AMPK[alpha]1-mediated mechanism. contraction; epitrochlearis muscle; hydrogen peroxide; hypoxanthine: xanthine oxidase