| 1. |
- Ahrén, Bo
(author)
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beta- and alpha-Cell Dysfunction in Subjects Developing Impaired Glucose Tolerance Outcome of a 12-Year Prospective Study in Postmenopausal Caucasian Women
- 2009
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:3, s. 726-731
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Journal article (peer-reviewed)abstract
- OBJECTIVE-This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period. RESEARCH DESIGN AND METHODS-At baseline and after 3, 8, and 12 years, glucose tolerance (75-g oral glucose tolerance test), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin and glucagon secretion (2- to 5-min responses to 5 g arginine i.v. at fasting, 14 and >25 mmol/l glucose) were determined in 53 healthy Caucasian women (aged 58 years at. baseline) who all had NGT at baseline. RESULTS-During the 12-year period, 26 subjects developed IGT, whereas the remaining 27 subjects maintained NGT throughout the 12-year period. Subjects developing IGT had lower insulin sensitivity than those maintaining NGT in the tests preceding diagnosis of IGT (P <= 0.05). When judged in relation to insulin sensitivity, P-cell glucose sensitivity and maximal insulin secretion were lower in those who later developed IGT than in those maintaining NGT at all tests (P : 0.05). Furthermore, subject's who developed IGT had defective suppression of glucagon secretion by glucose in the test preceding diagnosis of IGT when they still had NGT (P : 0.05). CONCLUSIONS-beta- and alpha-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifeste as impaired glucose sensitivity of the beta- and (x-cells and reduced maximal insulin secretion. Diabetes 58:726-731, 2009
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| 2. |
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| 3. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(author)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
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In: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Journal article (peer-reviewed)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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| 4. |
- Færch, Kristine, et al.
(author)
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Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation
- 2016
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:11, s. 3473-3481
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Journal article (peer-reviewed)abstract
- Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.
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| 5. |
- García, Maria C, et al.
(author)
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Mature-onset obesity in interleukin-1 receptor I knockout mice.
- 2006
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:5, s. 1205-13
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Journal article (peer-reviewed)abstract
- Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity.
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| 6. |
- Henquin, JC, et al.
(author)
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In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse - Pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells
- 2006
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 55:2, s. 441-451
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Journal article (peer-reviewed)abstract
- The mechanisms underlying biphasic insulin secretion have not been completely elucidated. We compared the pattern of plasma insulin changes during hyperglycemic clamps in mice to that of glucose-induced insulin secretion and cytosolic calcium concentration ([Ca2+](c)) changes in perifused mouse islets. Anesthetized mice were infused with glucose to clamp blood glucose at 8.5 (baseline), 11.1, 16.7, or 30 mmol/l. A first-phase insulin response consistently peaked at 1 min, and a slowly ascending second phase occurred at 16.7 and 30 mmol/l glucose. Glucose-induced insulin secretion in vivo is thus biphasic, with a similarly increasing second phase in the mouse as in humans. In vitro, square-wave stimulation from a baseline of 3 mmol/l glucose induced similar biphasic insulin secretion and [Ca2+](c) increases, with sustained and flat second phases. The glucose dependency (3-30 mmol/l) of both changes was sigmoidal with, however, a shift to the right of the relation for insulin secretion compared with that for [Ca2+](c). The maximum [Ca2+](c), increase was achieved by glucose concentrations, causing half-maximum insulin secretion. Because this was true for both phases, we propose that contrary to current concepts, amplifying signals are also implicated in first-phase glucose-induced insulin secretion. To mimic in vivo conditions, islets were stimulated with high glucose after being initially perifused with 8.5 instead of 3.0 mmol/l glucose. First-phase insulin secretion induced by glucose at 11.1, 16.7, and 30 mmol/l was decreased by similar to 50%, an inhibition that could not be explained by commensurate decreases in [Ca2+](c) or in the pool of readily releasable granules. Also unexpected was the gradually ascending pattern of the second phase, now similar to that in vivo. These observations indicated that variations in prestimulatory glucose can secondarily affect the magnitude and pattern of subsequent glucose-induced insulin secretion.
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| 7. |
- Huang, Xudong, et al.
(author)
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Impaired cathepsin L gene expression in skeletal muscle is associated with type 2 diabetes.
- 2003
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 52:9, s. 2411-2418
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Journal article (peer-reviewed)abstract
- To identify abnormally expressed genes associated with muscle insulin resistance or type 2 diabetes, we screened the mRNA populations using cDNA differential display combined with relative RT-PCR analysis from muscle biopsies of diabetes-prone C57BL/6J and diabetes-resistant NMRI mice fed with a high-fat or normal diet for 3 or 15 months. Six abnormally expressed genes were isolated from the mice after a 3-month fat feeding; one of them was cathepsin L. No significant difference in mRNA levels of these genes was observed between fat- and normal-diet conditions in either strains. However, cathepsin L mRNA levels in muscle were higher in normal diet–fed C57BL/6J mice compared with normal diet–fed NMRI mice at 3 months (0.72 ± 0.04 vs. 0.51 ± 0.04 relative units, P < 0.01, n = 8–10) and at 15 months (0.41 ± 0.05 vs. 0.27 ± 0.04 relative units, P = 0.01, n = 9–10). Further, cathepsin L mRNA levels in muscle correlated inversely with plasma glucose in both strains regardless of diets at 3 (r = −0.49, P < 0.01, n = 31) and 15 (r = −0.42, P = 0.007, n = 39) months. To study whether cathepsin L plays a role in human diabetes, we measured cathepsin L mRNA levels in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and from 12 control subjects. Basal cathepsin L mRNA levels were not significantly different between the study groups. Insulin infusion increased cathepsin L mRNA levels in control subjects from 1.03 ± 0.30 to 1.90 ± 0.32 relative units (P = 0.03). Postclamp cathepsin L mRNA levels were lower in diabetic twins but similar in nondiabetic twins compared with control subjects (0.66 ± 0.22, 1.16 ± 0.18 vs. 1.38 ± 0.21 relative units, P < 0.02, NS, respectively). Further, postclamp cathepsin L mRNA levels were correlated with insulin-mediated glucose uptake (r = 0.37, P = 0.03), particularly, with glucose oxidation (r = 0.37, P = 0.03), and fasting glucose concentrations (r = −0.45, P < 0.01) across all three study groups. In conclusion, muscle cathepsin L gene expression is increased in diabetes-prone mice and related to glucose tolerance. In humans, insulin-stimulated cathepsin L expression in skeletal muscle is impaired in diabetic but not in nondiabetic monozygotic twins, suggesting that the changes may be secondary to impaired glucose metabolism.
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| 8. |
- Mulder, Hindrik, et al.
(author)
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Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion.
- 2004
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:1, s. 122-128
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Journal article (peer-reviewed)abstract
- Lipids may serve as coupling factors in KATP-independent glucose sensing in β-cells. We have previously demonstrated that β-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether β-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in KATP-independent glucose sensing has been perturbed. Thus, β-cell lipase activity is involved in GSIS, emphasizing the important role of β-cell lipid metabolism for insulin secretion.
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| 9. |
- Omar, Bilal, et al.
(author)
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Fibroblast Growth Factor 21 (FGF21) and Glucagon Like-Peptide 1 Contribute to Diabetes Resistance in Glucagon Receptor Deficient Mice.
- 2014
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:1, s. 101-110
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Journal article (peer-reviewed)abstract
- Mice genetically deficient in the glucagon receptor (Gcgr(-/-)) show improved glucose tolerance, insulin sensitivity and α-cell hyperplasia. In addition, Gcgr(-/-) mice do not develop diabetes after chemical destruction of β-cells. Since fibroblast growth factor 21 (FGF21) has insulin independent glucose lowering properties we investigated whether FGF21 was contributing to diabetes resistance in insulin deficient Gcgr(-/-) mice. Plasma FGF21 was 25 fold higher in Gcgr(-/-) mice than in wild type mice. FGF21 was found to be expressed in pancreatic β- and α-cells, with high expression in the hyperplastic α-cells of Gcgr(-/-) mice. FGF21 expression was also significantly increased in liver and adipose tissue of Gcgr(-/-) mice. To investigate the potential anti-diabetic actions of FGF21 in insulin deficient Gcgr(-/-) mice, an FGF21 neutralizing antibody was administered prior to oral glucose tolerance tests (OGTT). FGF21 neutralization caused a decline in glucose tolerance in insulin deficient Gcgr(-/-) mice during the OGTT. Despite this decline, insulin deficient Gcgr(-/-) mice did not develop hyperglycemia. Glucagon-like peptide (GLP-1) also has insulin independent glucose lowering properties and elevated circulating GLP-1 is a known characteristic of Gcgr(-/-) mice. Neutralization of FGF21 while concurrently blocking the GLP-1 receptor with the antagonist Exendin9-39 resulted in significant hyperglycemia in insulin deficient Gcgr(-/-) mice, while Exendin9-39 alone did not. In conclusion, FGF21 acts additively with GLP-1 to prevent insulinopenic diabetes in mice lacking glucagon action.
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| 10. |
- Omar, Bilal, et al.
(author)
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Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors.
- 2014
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:7, s. 2196-2202
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Journal article (peer-reviewed)abstract
- Dipeptidyl peptidase (DPP)-4 inhibition is a glucose-lowering treatment for type 2 diabetes. The classical mechanism for DPP-4 inhibitors is that they inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, in turn increasing glucose utilization and diminishing hepatic glucose production, which, through reduction in postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but also to a limited degree in humans have found additional mechanisms for DPP-4 inhibitors that may contribute to their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which prevents inactivation of newly released GLP-1, which in turn augments GLP-1-induced activations of autonomic nerves and results in high portal GLP-1 levels, resulting in inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents inactivation of locally produced intact GLP-1 in the islets, thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation; and 3) prevention of the inactivation of other bioactive peptides apart from GLP-1, such as glucose-dependent insulinotropic polypeptide, stromal-derived factor-1α, and pituitary adenylate cyclase-activating polypeptide, which may improve islet function. These pleiotropic effects may contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.
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