Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo

Kawamori, Dan; Kurpad, Amarnath J.; Hu, Jiang; Liew, Chong Wee; Shih, Judy L.; Ford, Ethan; Herrera, Pedro Luis; Polonsky, Kenneth S.; McGuinness, Owen P.; Kulkarni, Rohit

doi:10.1016/j.cmet.2009.02.007

Cited by 285 publications

(306 citation statements)

References 66 publications

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“…4 A and B), suggesting that leptin suppresses glucagon via CNS LEPRdescending pathways in the context of insulin deficiency. Alternatively, these glucagon improvements may be secondary to reduced hyperglycemia, because it has been suggested that without insulin, glucose stimulates glucagon secretion from α-cells (38)(39)(40)(41). Consistent with reduced glucagon, the hepatic content of phosphoenolpyruvate carboxykinase 1 (an enzyme that mediates the first catalytic reaction in the gluconeogenic pathway, the amounts of which are increased by glucagon) was also elevated in T1D-icv-PBS mice but was normal in T1D-icv-Leptin-50 mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

222

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Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

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Section: Resultsmentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

222

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Section: Adulthoodmentioning

confidence: 99%

“…Altered alpha cell function in mice, secondary to alpha cellspecific knockout of insulin receptors (alpha-IRKO), has been reported to either directly or indirectly influence beta cell proliferation in the mutants [28]. Lack of glucagon itself is reported to induce alpha cell hyperplasia [29].…”

Section: Prenatal and Neonatal Periodmentioning

confidence: 99%

“…Several groups, including ours, have reported on the significance of insulin/IGF-1 signalling in the regulation of both beta and alpha cells [66,28]. A role for insulin signalling in the regulation of alpha cell function and mass is evident from analyses of alpha-IRKO mice [28]. Interestingly, the mutant mice exhibited hyperglucagonaemia, glucose intolerance and an age-dependent progressive increase in beta cell area, while alpha cell area was unchanged leading to a decrease in relative alpha cell area [70].…”

Section: Adulthoodmentioning

confidence: 99%

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The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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“…[22][23][24] Notably, in humans not only islet a-cells but also β-cells express CADM1 on the cell membrane. 7 Therefore, CADM1 is likely to contribute to the establishment of GJIC not only among a-cells but also among β-cells via homophilic binding.…”

Section: Do Not Distributementioning

confidence: 99%

Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

Ito

Ichiyanagi

Ikeda

et al. 2012

Islets

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Keywords: connexin, cell-cell interaction, Necl-2, hyperglucagonemia, diabetes mellitus, SynCAMCell adhesion molecule-1 (CADM1) is a recently identified adhesion molecule of pancreatic islet a-cells that mediates nerve-a-cell interactions via trans-homophilic binding and serves anatomical units for the autonomic control of glucagon secretion. CADM1 also mediates attachment between adjacent a-cells. Since gap junctional intercellular communication (GJIC) among islet cells is essential for islet hormone secretion, we examined whether CADM1 promotes GJIC among a-cells and subsequently participates in glucagon secretion regulation. Dye transfer assays using aTC6 mouse a-cells, which endogenously express CADM1, supported this possibility; efficient cell-to-cell spread of gap junction-permeable dye was detected in clusters of aTC6 cells transfected with nonspecific, but not with CADM1-targeting, siRNA. Immunocytochemical analysis of connexin 36, a major component of the gap junction among aTC6 cells, revealed that it was localized exclusively to the cell membrane in CADM1-non-targeted aTC6 cells, but diffusely to the cytoplasm in CADM1-targeted cells. Next, we incubated CADM1-targeted and non-targeted aTC6 cells in a medium containing 1 mM glucose and 200 mM arginine for 30 min to induce glucagon secretion, and found that the targeted cells secreted three times more glucagon than did the non-targeted. We conducted similar experiments using pancreatic islets that were freshly isolated from wild-type and CADM1-knockout mice, and expressed glucagon secretion as ratios relative to baseline values. The increase in ratio was larger in CADM1-knockout islets than in wild-type islets. These results suggest that CADM1 may serve as a volume limiter of glucagon secretion by sustaining a-cell attachment necessary for efficient GJIC.

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Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo

Cited by 285 publications

References 66 publications

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon

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