| 1. |
- Amrutkar, Manoj, et al.
(författare)
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Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:8, s. 2791-2804
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(-/-) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(-/-) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes.
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| 2. |
- Amrutkar, Manoj, et al.
(författare)
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Protein kinase STK25 regulates hepatic lipid partitioning and progression of liver steatosis and NASH
- 2015
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Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:4, s. 1564-1576
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease, and 10% to 20% of NAFLD patients progress to nonalcoholic steatohepatitis (NASH). The molecular pathways controlling progression to NAFLD/NASH remain poorly understood. We recently identified serine/threonine protein kinase 25 (STK25) as a regulator of whole-body insulin and glucose homeostasis. This study investigates the role of STK25 in liver lipid accumulation and NASH. Stk25 transgenic mice challenged with a high-fat diet displayed a dramatic increase in liver steatosis and hepatic insulin resistance compared to wild-type siblings. Focal fibrosis, hepatocellular damage, and inflammation were readily seen in transgenic but not wild-type livers. Transgenic livers displayed reduced beta-oxidation and triacylglycerol secretion, while lipid uptake and synthesis remained unchanged. STK25 was associated with lipid droplets, colocalizing with the main hepatic lipid droplet-coating protein adipose differentiation-related protein, the level of which was increased 3.8 +/- 0.7-fold in transgenic livers (P < 0.01), while a key hepatic lipase, adipose triacylglycerol lipase, was translocated from the lipid droplets surface to the cytoplasm, providing the likely mechanism underlying the effect of STK25. In summary, STK25 is a lipid droplet-associated protein that promotes NAFLD through control of lipid release from the droplets for beta-oxidation and triacylglycerol secretion. STK25 also drives pathogenesis of NASH.
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| 3. |
- Andersson, Christian X, 1973, et al.
(författare)
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Inflamed adipose tissue, insulin resistance and vascular injury
- 2008
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Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.
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| 4. |
- Andersson, Christian X, 1973, et al.
(författare)
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Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes
- 2007
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Ingår i: J Biol Chem. - 0021-9258. ; 282:13, s. 9430-5
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.
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| 5. |
- Arner, P., et al.
(författare)
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Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis
- 2011
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Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition. CONCLUSIONS/SIGNIFICANCE: Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.
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| 6. |
- Attramadal, Havard, et al.
(författare)
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Report on the 11th international workshop on the CCN family of genes, Nice, October 20-24, 2022
- 2023
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Ingår i: JOURNAL OF CELL COMMUNICATION AND SIGNALING. - : Springer Science and Business Media LLC. - 1873-9601 .- 1873-961X. ; 17:1, s. 7-11
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Tidskriftsartikel (refereegranskat)abstract
- In celebration of the twentieth anniversary of the inception of the CCN society, and of the first post-Covid-19 live meeting, the executive board of the ICCNS had chosen Nice as the venue for the 11th International workshop on the CCN family of genes. On this occasion participation in the meeting was extended to colleagues from other cell signaling fields who were invited to present both an overview of their work and the future directions of their laboratory. Also, for the first time, the members of the JCCS Editorial Board were invited to participate in a JCCS special session during which all aspects of the journal & laquo; life & raquo; were addressed and opened to free critical discussion. The scientific presentations and the discussions that followed showed once more that an expansion of the session topics was beneficial to the quality of the meeting and confirmed that the ARBIOCOM project discussed last April in Nice was now on track to be launched in 2023. The participants unanimously welcomed Professor Attramadal's proposition to organize the 2024, 12th International CCN workshop in Oslo, Norway.
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| 7. |
- Axelsen, Mette, 1965, et al.
(författare)
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Bedtime uncooked cornstarch supplement prevents nocturnal hypoglycaemia in intensively treated type 1 diabetes subjects.
- 1999
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Ingår i: Journal of internal medicine. - 0954-6820. ; 245:3, s. 229-36
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The present study tests two interrelated hypotheses: (1) that bedtime ingestion of uncooked cornstarch exerts a lower and delayed nocturnal blood glucose peak compared with a conventional snack; (2) that bedtime carbohydrate supplement, administered as uncooked cornstarch, prevents nocturnal hypoglycaemia without altering metabolic control in intensively treated type 1 diabetes (IDDM) patients. DESIGN AND SUBJECTS: The above hypotheses were tested separately (1) by pooling and analysing data from two overnight studies of comparable groups of patients with non-insulin dependent diabetes mellitus (NIDDM) (14 and 10 patients, respectively), and (2) by a double-blind, randomized 4-week cross-over study in 12 intensively treated IDDM patients. SETTING: Sahlgrenska University Hospital, Göteborg. Sweden. INTERVENTIONS: (1) Ingestion of uncooked cornstarch and wholemeal bread (0.6 g of carbohydrates kg-1 body weight) and carbohydrate-free placebo at 22.00 h. (2) Intake of uncooked cornstarch (0.3 g kg-1 body weight) and carbohydrate-free placebo at 23.00 h. MAIN OUTCOME MEASURES: (1) Nocturnal glucose and insulin levels; (2) frequency of self-estimated hypoglycaemia (blood glucose [BG] levels < 3.0 mmol L-1) at 03.00 h, HbA1c and fasting lipids. RESULTS: Bedtime uncooked cornstarch ingestion led to a lower (2.9 +/- 0.5 vs. 5.2 +/- 0.6 mM, P = 0.01) and delayed (4.3 +/- 0.6 vs. 2.0 +/- 0.0 h, P < 0.01) BG peak, compared with a conventional snack, in NIDDM patients. Four weeks of bedtime uncooked cornstarch supplement, as compared with placebo, led to a 70% reduction in the frequency of self-estimated hypoglycaemia at 03.00 h (P < 0.05), without affecting HbA1c or fasting lipids in IDDM patients. CONCLUSIONS: Uncooked cornstarch, ingested at bedtime, mimicked the nocturnal glucose utilization profile following insulin replacement, with a peak in blood glucose after 4 h. In IDDM patients, bedtime uncooked cornstarch supplement diminished the number of self-estimated hypoglycaemic episodes, without adversely affecting HbA1c and lipid levels. Hence, bedtime uncooked cornstarch ingestion may be feasible to prevent a mid-nocturnal glycaemic decline following insulin replacement in IDDM and, based on the nocturnal blood glucose profile, may also be preferable compared with conventional snacks.
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| 8. |
- Axelsen, Mette, 1965, et al.
(författare)
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Breakfast glycaemic response in patients with type 2 diabetes: effects of bedtime dietary carbohydrates.
- 1999
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Ingår i: European journal of clinical nutrition. - 0954-3007. ; 53:9, s. 706-10
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Bedtime carbohydrate (CHO) intake in patients with type-2 diabetes may improve glucose tolerance at breakfast the next morning. We examined the 'overnight second-meal effect' of bedtime supplements containing 'rapid' or 'slow' CHOs. DESIGN: Randomized cross-over study with three test-periods, each consisting of two days on a standardized diet, followed by a breakfast tolerance test on the third morning. SETTING: The Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. SUBJECTS: Sixteen patients with type 2 diabetes on oral agents and/or diet. INTERVENTIONS: Two different bedtime (22.00 h) CHO supplements (0.46 g available CHO/kg body weight) were compared to a starch-free placebo ('normal' food regimen). The CHOs were provided as uncooked cornstarch (slow-release CHOs) or white bread (rapid CHOs). RESULTS: On the mornings after different bedtime meals we found similar fasting glucose, insulin, free fatty acid and lactate levels. However, the glycaemic response after breakfast was 21% less after uncooked cornstarch compared to placebo ingestion at bedtime (406 +/- 46 vs 511 +/- 61 mmol min l(-1), P < 0.01). In contrast, it did not differ when the evening meal consisted of white bread (451 +/- 57 mmol min l(-1)) compared to placebo. According to an in vitro analysis, uncooked cornstarch contained approximately 4 times more slowly digestible starch as compared to white bread. CONCLUSIONS: A bedtime meal providing uncooked cornstarch improved breakfast tolerance the next morning while, in contrast, this was not found following a bedtime meal of white bread. The results are consistent, therefore, with the concept that an increased intake of slowly digestible carbohydrates exert an overnight second-meal effect in patients with type 2 diabetes.
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| 9. |
- Axelsen, Mette, 1965, et al.
(författare)
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Lipid intolerance in smokers
- 1995
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Ingår i: J Intern Med. - 0954-6820. ; 237:5, s. 449-55
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES. Smokers have recently been shown to be insulin resistant and to exhibit several characteristics of the insulin resistance syndrome (IRS). In this study, we assessed fasting and postprandial lipid levels in healthy, normolipidaemic, chronic smokers and a matched group of non-smoking individuals. DESIGN. A standardized mixed meal (containing 3.78 MJ and 51 g of fat) was given in the morning after an overnight fast. The smokers were either abstinent from tobacco for 48 h or were allowed to smoke freely, including being allowed to smoke six cigarettes during the study. SUBJECTS. Twenty-two middle-aged, healthy male subjects, nine habitual smokers and 13 non-smoking control subjects, were recruited to the study. The smokers had all been smoking at least 10 cigarettes per day for at least 10 years. RESULTS. The smokers exhibited a lipid intolerance in that their postprandial increase in triglyceride levels was more than 50% higher than in the non-smokers' group. This lipid intolerance could not be discerned in the postabsorptive state because the fasting triglyceride levels were the same in both groups, while the smokers had significantly lower high-density lipoprotein (HDL) cholesterol. The peak postprandial triglyceride level correlated closely and negatively with fasting HDL cholesterol, indicating an impaired lipolytic removal capacity in smokers. CONCLUSIONS. Healthy, normotriglyceridaemic smokers exhibit an abnormal postprandial lipid metabolism consistent with lipid intolerance. It is suggested that postprandial hyperlipidaemia is a characteristic trait of the insulin resistance syndrome and that the defect in lipid removal is related to the low HDL cholesterol in this syndrome. The insulin resistance syndrome is likely to be an important reason for the increased propensity for cardiovascular disease in smokers.
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| 10. |
- Axelsen, Mette, 1965, et al.
(författare)
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Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.
- 1999
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Ingår i: Annals of internal medicine. - 0003-4819 .- 1539-3704. ; 131:1, s. 27-31
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.
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