| 1. |
- Abdel-Halim, SM, et al.
(författare)
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Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes
- 1998
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 47:3, s. 498-504
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Tidskriftsartikel (refereegranskat)abstract
- Glucose-induced insulin release is decreased in the spontaneously diabetic GK rat, a nonobese rodent model of type 2 diabetes. Forskolin restores the impaired insulin release in both the isolated perfused pancreas and isolated islets from these rats (Abdel-Halim et al., Diabetes 45:934-940, 1996). We demonstrate here that the insulinotropic effect of forskolin in the GK rat is due to increased generation of cAMP and that it is associated with overexpression of adenylyl cyclase (AC)-III mRNA and gene mutations. The AC-III mRNA overexpression was demonstrated by in situ hybridization using oligonucleotide probes binding to different regions of the rat AC-III mRNA. It was associated with the presence of two point mutations identified at positions -28 bp (A --> G) and -358 bp (A --> C) of the promoter region of the AC-III gene and was demonstrable in both GK rat islets and peripheral blood cells. Transfection of COS cells with a luciferase reporter gene system revealed up to 25-fold increased promoter activity of GK AC-III promoter when compared with normal rat promoter (P < 0.0001). In conclusion, forskolin restores the impaired insulin release in islets of the GK rat through enhanced cAMP generation. This is linked to overexpression of AC-III mRNA in GK islets due to two functional point mutations in the promoter region of the AC-III gene.
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| 2. |
- Abrahamsson, Niclas, 1976-, et al.
(författare)
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Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:9, s. 2667-2675
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Tidskriftsartikel (refereegranskat)abstract
- Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.
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| 3. |
- Ahlqvist, Emma, et al.
(författare)
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A link between GIP and osteopontin in adipose tissue and insulin resistance.
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:6, s. 2088-2094
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Tidskriftsartikel (refereegranskat)abstract
- Low grade inflammation in obesity is associated with accumulation of the macrophagederived cytokine osteopontin in adipose tissue and induction of local as well as systemic insulin resistance. Since GIP (glucose-dependent insulinotropic polypeptide) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate osteopontin (OPN) expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13±}0.04 vs 0.04±}0.01, P<0.05) and correlated inversely with measures of insulin sensitivity (r=-0.24, P=0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with lower amount of the exon 9 containing isoform required for transmembrane activity. Carriers of the A-allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone, but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of GIPR rs10423928 A-allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.
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| 4. |
- Ahmad, Shafqat, et al.
(författare)
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Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome : A Multi-Cohort Nontargeted Metabolomics Observational and Mendelian Randomization Study
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 71:2, s. 329-339
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.
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| 5. |
- Ahrén, Bo
(författare)
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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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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:3, s. 726-731
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Tidskriftsartikel (refereegranskat)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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| 6. |
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| 7. |
- Al-Majdoub, Mahmoud, et al.
(författare)
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Metabolite profiling of LADA challenges the view of a metabolically distinct subtype
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 806-814
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Tidskriftsartikel (refereegranskat)abstract
- Latent autoimmune diabetes in adults (LADA) usually refers to GAD65 autoantibodies (GADAb)-positive diabetes with onset after 35 years of age and no insulin treatment within the first 6 months after diagnosis. However, it is not always easy to distinguish LADA fromtype 1 or type 2 diabetes. In this study, we examined whether metabolite profiling could help to distinguish LADA (n = 50) from type 1 diabetes (n = 50) and type 2 diabetes (n = 50). Of 123 identified metabolites, 99 differed between the diabetes types. However, no unique metabolite profile could be identified for any of the types. Instead, the metabolome varied along a C-peptide-driven continuum from type 1 diabetes via LADA to type 2 diabetes. LADA was more similar to type 2 diabetes than to type 1 diabetes. In a principal component analysis, LADA patients overlapping with type 1 diabetes progressed faster to insulin therapy than those overlapping with type 2 diabetes. In conclusion, we could not find any unique metabolite profile distinguishing LADA from type 1 and type 2 diabetes. Rather, LADA was metabolically an intermediate of type 1 and type 2 diabetes, with those patients closer to the former showing a faster progression to insulin therapy than those closer to the latter.
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| 8. |
- Alanentalo, Tomas, et al.
(författare)
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Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:7, s. 1756-1764
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.
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| 9. |
- Alenkvist, Ida, et al.
(författare)
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Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming for Exocytosis
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:10, s. 2610-2622
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Tidskriftsartikel (refereegranskat)abstract
- Epac is a cAMP-activated guanine nucleotide exchange factor that mediates cAMP signaling in various types of cells, including -cells, where it is involved in the control of insulin secretion. Upon activation, the protein redistributes to the plasma membrane, but the underlying molecular mechanisms and functional consequences are unclear. Using quantitative high-resolution microscopy, we found that cAMP elevation caused rapid binding of Epac2A to the -cell plasma membrane, where it accumulated specifically at secretory granules and rendered them more prone to undergo exocytosis. cAMP-dependent membrane binding required the high-affinity cyclic nucleotide-binding (CNB) and Ras association domains, but not the disheveled-Egl-10-pleckstrin domain. Although the N-terminal low-affinity CNB domain (CNB-A) was dispensable for the translocation to the membrane, it was critical for directing Epac2A to the granule sites. Epac1, which lacks the CNB-A domain, was recruited to the plasma membrane but did not accumulate at granules. We conclude that Epac2A controls secretory granule release by binding to the exocytosis machinery, an effect that is enhanced by prior cAMP-dependent accumulation of the protein at the plasma membrane.
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| 10. |
- Almby, Kristina E., et al.
(författare)
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Effects of Gastric Bypass Surgery on the Brain : Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 70:6, s. 1265-1277
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Tidskriftsartikel (refereegranskat)abstract
- While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.
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