PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells

Hashimoto, Naoko; Kido, Yoshiaki; Uchida, Tsuyoshi; Matsuda, Tomokazu; Suzuki, Kazuhisa; Inoue, Hiroshi; Matsumoto, Michihiro; Ogawa, Wataru; Maeda, Sakan; Fujihara, Hiroaki; Ueta, Yoichi; Uchiyama, Yasuo; Akimoto, Kazunori; Ohno, Shigeo; Noda, Tetsuo; Kasuga, Masato

doi:10.1172/jci22232

Cited by 59 publications

(51 citation statements)

References 56 publications

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“…By contrast, exercise plays a crucial role in diabetic treatment, not only by lessening insulin resistance, but also through potentiating b-cell function and mass via enhancement of the insulin/IGF-I signaling cascade. Enhanced signaling promoted the expansion of b-cell mass by increasing hyperplasia via increased b-cell proliferation and decreased apoptosis (Hennige et al 2003, Hashimoto et al 2005. Thus, hyperplasia is necessary in order to strengthen b-cell function to compensate for insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

Choi

Jang

Hong

et al. 2006

Journal of Endocrinology

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Long-term dexamethasone (DEX) treatment is well known for its ability to increase insulin resistance in liver and adipose tissues leading to hyperinsulinemia. On the other hand, exercise enhances peripheral insulin sensitivity. However, it is not clear whether DEX and/or exercise affect b-cell mass and function in diabetic rats, and whether their effects can be associated with the modulation of the insulin/IGF-I signaling cascade in pancreatic b-cells. After an 8-week study, whole body glucose disposal rates in 90% pancreatectomized (Px) and sham-operated male rats decreased with a high dose treatment of DEX (0$1mg DEX/kg body weight/day)(HDEX) treatment, while disposal rates increased with exercise. First-phase insulin secretion was decreased and delayed by DEX via the impairment of the glucose-sensing mechanism in b-cells, while exercise reversed the impairment of first-phase insulin secretion caused by DEX, suggesting ameliorated b-cell functions. However, exercise and DEX did not alter secondphase insulin secretion except for the fact that HDEX decreased insulin secretion at 120 min during hyperglycemic clamp in Px rats. Unlike b-cell functions, DEX and exercise exhibited increased pancreatic b-cell mass in two different pathways. Only exercise, through increased proliferation and decreased apoptosis, increased b-cell mass via hyperplasia, which resulted from an enhanced insulin/IGF-I signaling cascade by insulin receptor substrate 2 induction. By contrast, DEX expanded b-cell mass via hypertrophy and neogenesis from precursor cells, rather than increasing proliferation and decreasing apoptosis. In conclusion, the improvement of b-cell function and survival via the activation of an insulin/IGF-I signaling cascade due to exercise has a crucial role in preventing the development and progression of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

Choi

Jang

Hong

et al. 2006

Journal of Endocrinology

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“…The area of ␤ cells was determined by hematoxylineosin staining of pancreatic sections as described previously (29).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of KLF15 Transcription Factor in Adipocytes of Mice Results in Down-regulation of SCD1 Protein Expression in Adipocytes and Consequent Enhancement of Glucose-induced Insulin Secretion

Nagare

Sakaue

Matsumoto

et al. 2011

Journal of Biological Chemistry

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Krüppel-like factor 15 (KLF15), a member of the Krüppel-like factor family of transcription factors, has been found to play diverse roles in adipocytes in vitro. However, little is known of the function of KLF15 in adipocytes in vivo. We have now found that the expression of KLF15 in adipose tissue is down-regulated in obese mice, and we therefore generated adipose tissue-specific KLF15 transgenic (aP2-KLF15 Tg) mice to investigate the possible contribution of KLF15 to various pathological conditions associated with obesity in vivo. The aP2-KLF15 Tg mice manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. Furthermore, this enhancement of insulin secretion was shown to result from down-regulation of the expression of stearoyl-CoA desaturase 1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in white adipose tissue of aP2-KLF15 Tg mice exhibited increased oxidative stress in white adipose tissue and reduced insulin secretion with hyperglycemia. Our data thus provide an example of cross-talk between white adipose tissue and pancreatic ␤ cells mediated through modulation of oxidative stress.Obesity is characterized by an increased amount of adipose tissue and is associated with various complications, including insulin resistance, type 2 diabetes, dyslipidemia, and atherosclerosis (1, 2). Mammals possess two types of adipose tissue, white adipose tissue (WAT) 3 and brown adipose tissue (BAT). White adipocytes play an important role in obesity by secreting numerous bioactive substances known as adipocytokines (or adipokines) as well as by storing energy in the form of triglyceride. Through the secretion of adipokines, white adipocytes affect other tissues, including the liver, skeletal muscle, ␤ cells of the pancreas, and the central nervous system. Brown adipocytes, which contain abundant mitochondria, also play an important role in obesity by dissipating energy through adaptive thermogenesis. Both white and brown adipocytes thus influence systemic energy metabolism (3).Krüppel-like factor 15 (KLF15), a member of the Krüppel-like factor family of transcription factors, was first identified as a molecule that binds to the promoter of the gene for CLC-K1, a kidney-specific CLC chloride channel (4). We and others subsequently showed that KLF15 regulates gene expression in various cell types, including adipocytes (5-7), myocytes (7,8), and hepatocytes (9, 10). Characterization of mice lacking KLF15 implicated this protein in the regulation of gluconeogenesis with amino acids as substrates (11). However, little is known of the role of KLF15 in adipose tissue in vivo.Stearoyl-CoA desaturase 1 (SCD1), a member of the fatty acid desaturase family, has recently been associated with obesity, diabetes, immune disorders, and inflammation (12, 13). Mice deficient in ...

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“…The use of PKC inhibitors has resulted in conflicting conclusions (Jones and Persaud, 1998). Recent studies of PKC isoform-selective knock-out mice have indicated important roles for PKCδ and -λ in insulin secretion (Hashimoto et al, 2005;Uchida et al, 2007). Deletion of PKCε did not affect normal glucose-induced insulin secretion, but amplified that in islets treated with fatty acids (Schmitz-Peiffer et al, 2007).…”

Section: Pip 2 and Signalling Via Phospholipase Cmentioning

confidence: 99%

Oscillatory control of insulin secretion

Tengholm

Gylfe

2009

Molecular and Cellular Endocrinology

163

169

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Pulsatile insulin secretionSince insulin is the only blood glucose-lowering hormone, its secretion is essential for glucose homeostasis, and disturbances are associated with glucose intolerance and diabetes.Glucose is the major stimulus for insulin release but secretion is enhanced also by other nutrients and is under stimulatory and inhibitory control by hormones and neurotransmitters.Although the external factors are essential determinants of insulin secretion, there are also input-independent variations in hormone release. Regular oscillations of the circulating insulin concentrations in normal subjects consequently occur without accompanying changes

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PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells

Cited by 59 publications

References 56 publications

Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

Overexpression of KLF15 Transcription Factor in Adipocytes of Mice Results in Down-regulation of SCD1 Protein Expression in Adipocytes and Consequent Enhancement of Glucose-induced Insulin Secretion

Oscillatory control of insulin secretion

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