Presently, routine screening misses many cases of prediabetes and early type 2 diabetes (T2D). Therefore, better biomarkers are needed for a simple and early detection of abnormalities of glucose ...metabolism and prediction of future T2D. Possible candidates for this include plasma or serum amino acids because glucose and amino acid metabolism are closely connected. This review presents the available evidence of this connectivity and discusses its clinical implications. First, we examine the underlying physiological, pre-analytical, and analytical issues. Then, we summarize results of human studies that evaluate amino acid levels as markers for insulin resistance, prediabetes, and future incident T2D. Finally, we illustrate the interconnection of amino acid levels and metabolic syndrome with our own data from a deeply phenotyped human cohort. We also discuss how amino acids may contribute to the pathophysiology of T2D. We conclude that elevated branched-chain amino acids and reduced glycine are currently the most robust and consistent amino acid markers for prediabetes, insulin resistance, and future T2D. Yet, we are cautious regarding the clinical potential even of these parameters because their discriminatory power is insufficient and their levels depend not only on glycemia, but also on other components of the metabolic syndrome. The identification of more precise intermediates of amino acid metabolism or combinations with other biomarkers will, therefore, be necessary to obtain in order to develop laboratory tests that can improve T2D screening.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background
Familial partial lipodystrophies are rare monogenic disorders that are often associated with diabetes. In such cases, it can be difficult to achieve glycaemic control.
Case report
We ...report a 34‐year old woman with familial partial lipodystrophy type 2 (Dunnigan) and diabetes; her hyperglycaemia persisted despite metformin treatment. A combined intravenous glucose tolerance–euglycaemic clamp test showed severe insulin resistance, as expected, but also showed strongly diminished first‐phase insulin secretion. After the latter finding, we added the glucagon‐like peptide‐1 receptor agonist liraglutide to the patient's treatment regimen, which rapidly normalized plasma glucose levels. HbA1c values <42 mmol/mol (6.0%) have now been maintained for over 4 years.
Conclusion
This case suggests that a glucagon‐like peptide‐1 receptor agonist may be a useful component of glucose‐lowering therapy in individuals with familial partial lipodystrophy and diabetes mellitus.
What's new?
In a case of familial partial lipodystrophy type 2 (Dunnigan) with diabetes, we found an insulin secretory defect in addition to the expected insulin resistance.
The addition of the glucagon‐like peptide 1 (GLP‐1) receptor agonist liraglutide to the patient's treatment regimen rapidly improved glycaemic control and the effect has been sustained for over 4 years.
GLP‐1 receptor agonists may be a useful treatment for individuals with familial partial lipodystrophy and diabetes.
Genetically engineered pigs are a promising source for islet cell transplantation in type 1 diabetes, but the strong human anti-pig immune response prevents its successful clinical application. Here ...we studied the efficacy of neonatal porcine islet-like cell clusters (NPICCs) overexpressing LEA29Y, a high-affinity variant of the T cell co-stimulation inhibitor CTLA-4Ig, to engraft and restore normoglycemia after transplantation into streptozotocin-diabetic NOD-SCID IL2rγ
(NSG) mice stably reconstituted with a human immune system. Transplantation of INSLEA29Y expressing NPICCs resulted in development of normal glucose tolerance (70.4%) and long-term maintenance of normoglycemia without administration of immunosuppressive drugs. All animals transplanted with wild-type NPICCs remained diabetic. Immunohistological examinations revealed a strong peri- and intragraft infiltration of wild-type NPICCs with human CD45
immune cells consisting of predominantly CD4
and CD8
lymphocytes and some CD68
macrophages and FoxP3
regulatory T cells. Significantly less infiltrating lymphocytes and only few macrophages were observed in animals transplanted with INSLEA29Y transgenic NPICCs. This is the first study providing evidence that beta cell-specific LEA29Y expression is effective for NPICC engraftment in the presence of a humanized immune system and it has a long-lasting protective effect on inhibition of human anti-pig xenoimmunity. Our findings may have important implications for the development of a low-toxic protocol for porcine islet transplantation in patients with type 1 diabetes.
Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On ...the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.
Low physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this ...population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass.
Cross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression.
Women pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5-136.5) vs. 141.0(128.5-159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ρ = -0.72 p<0.0001; VO2peak ρ = -0.16 p = 0.015; max. load ρ = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI).
Women with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels-independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectiveThe prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based ...on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30–79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects.MethodsData were obtained from the first follow-ups of the population-based Study of Health in Pomerania (SHIP; n=1392) and the Cooperative Health Research in the Region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies. Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC.ResultsThe frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A–C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects.ConclusionsA maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients.
Neonatal porcine islet-like cell clusters (NPICCs) are a promising source for islet cell transplantation. Excellent islet quality is important to achieve a cure for type 1 diabetes. We investigated ...formation of cell clusters from dispersed NPICCs on microwell cell culture plates, evaluated the composition of re-aggregated porcine islets (REPIs) and compared
function by transplantation into diabetic NOD-SCID IL2rγ
(NSG) mice with native NPICCs. Dissociation of NPICCs into single cells and re-aggregation resulted in the formation of uniform REPI clusters. A higher prevalence of normoglycemia was observed in diabetic NSG mice after transplantation with a limited number (
= 1500) of REPIs (85.7%) versus NPICCs (
= 1500) (33.3%) (
< 0.05). Transplanted REPIs and NPICCs displayed a similar architecture of endocrine and endothelial cells. Intraperitoneal glucose tolerance tests revealed an improved beta cell function after transplantation of 1500 REPIs (AUC glucose 0-120 min 6260 ± 305.3) as compared to transplantation of 3000 native NPICCs (AUC glucose 0-120 min 8073 ± 536.2) (
< 0.01). Re-aggregation of single cells from dissociated NPICCs generates cell clusters with excellent functionality and improved
function as compared to native NPICCs.
Type 1 diabetes (T1D) currently affects approximately 28 million patients with a rising incidence worldwide. Despite improvement of intensive insulin therapy, only a subgroup of patients reached ...near‐normal blood glucose control. Prospective studies have shown that 30–40% of patients with T1D are at risk to develop devastating micro‐ or macrovascular complications. In the intensive insulin treatment arm of DCCT/EDIC study the cumulative incidences of proliferative retinopathy, nephropathy and cardiovascular diseases were 21%, 9% and 9% after 30 years of diabetes, respectively 1. In addition, about 15% of patients with a disease history of 20–25 years have the problem of hypoglycemia unawareness due to lack of hormonal counter‐regulation 2. These serious complications lead to a significant reduction of life‐expectancy as compared to non‐diabetic individuals. Thus, there is an urgent need for more effective and durable management of diabetes.
Transplantation of human beta cells using isolated islets or pancreas provided evidence that T1D can be cured by cell replacement therapies. Pancreas transplantation results in a significant reduction of vascular complication and reduced total mortality 3. After islet cell transplantation 3‐year insulin independency, preserved graft function (detectable C‐peptide) and elimination of severe hypoglycemia have been reported in 23%, 52% and 70% by the collaborative islet transplant registry 4. However, the total number of islet allografts (<100/years) and pancreas transplants (approximately 1800/year) worldwide is insufficient in relation to the number of potential recipients in whom islet/pancreas transplantation may be beneficial or even life‐saving.
In the last years there have been impressive advances in the field of beta cell generation from induced pluripotent stem cells/embryonic stem cells and xenograft transplantation. It has been shown that novel immunosuppressive regimen can induce long‐lasting pig islet survival in nonhuman primates 5,6 and the use of fetal pig pancreas reduces immunogenicity 7. Transgenic pigs expressing immunosuppressive and cytoprotective factors in beta cells have been generated. In addition, novel techniques of islet encapsulation in biochambers may allow long‐term islet function and pathogen‐free pig herds have been recently established to overcome the problem of zoonosis. The use of pig islets has additional advantages: (i) pig insulin is safe since it has been used for decades in the treatment of T1D; (ii) porcine pancreas is easily available on demand making it possible to reduce ischemia injury and pretreatment of recipients; (iii) pig islets do respond to glucose in a similar way as human islets. The last two points strongly favor pig islets as compared to neo‐beta cells derived from stem cells, which were reported to be not fully matured and possess the risk of tumor formation (teratomas) 8,9.
The striking advances in pig islet transplantation suggest that it may be possible to overcome the major immunological barriers to pig islets in recipients so that clinical trials can be started in humans within the next years. Therefore, porcine islet xenografts may be the most realistic option to offer cell replacement therapy to a higher number of patients with T1D at risk for severe diabetes‐associated complications. When this approach is successful the large‐scale availability of pig islets would also open the window for other applications such as transplantation in insulin‐treated patients with type 2 diabetes in whom insulin resistance currently excludes islet cells transplantation due to the demand of high insulin levels/high number of islets.
References
1. Dcct/EdicResearch Group. Modern‐day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009; 169: 1307–1316.
2. Pedersen‐Bjergaard U, Pramming S, Heller SRet al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev 2004; 20: 479–486.
3. Sollinger HW, Odorico JS, Becker YTet al. One thousand simultaneous pancreas‐kidney transplants at a single center with 22‐year follow‐up. Ann Surg 2009 Aug 27. Epub ahead of print
4. Alejandro R, Barton FB, Hering BJet al. 2008 Update from the collaborative islet transplant registry. Transplantation 2008; 86: 1783–1788.
5. Hering BJ, Wijkstrom M, Graham MLet al. Prolonged diabetes reversal after intraportal xenotransplantation of wild‐type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006; 12: 301–303.
6. Cardona K, Korbutt GS, Milas Zet al. Long‐term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 2006; 12: 304–306.
7. Hecht G, Eventov‐Friedman S, Rosen Cet al. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model. Proc Natl Acad Sci 2009; 106: 8659–8664.
8. Kroon E, Martinson LA, Kadoya Ket al. Pancreatic endoderm derived from human embryonic stem cells generates glucose‐responsive insulin‐secreting cells in vivo. Nat Biotechnol 2008; 26: 443–452.
9. Maehr R, Chen S, Snitow Met al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci 2009; 106: 15768–15773.
Aims/hypothesis
Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. ...Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI.
Methods
The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration.
Results
Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (
p
< 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (
p
< 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (
p
< 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (
p
< 0.04).
Conclusions/interpretation
Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.
Aldosterone excess in the context of primary aldosteronism (PA) has been associated with impaired glucose tolerance and diabetes mellitus. We retrospectively assessed the prevalence of diabetes ...mellitus in patients from the German Conn's Register and compared the data with those from hypertensive subjects of a population-based survey. In a case-control study, we have compared 638 patients with PA from the German Conn's registry who were treated in 6 German centers with 897 hypertensive control subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg (KORA). The samples were matched for age, sex, and blood pressure in a 1:1 ratio. Risk factors associated with the presence of diabetes mellitus were calculated in 638 patients with PA and 897 hypertensive controls. In the case control study, the diabetes prevalence was calculated in 338 cases and controls. In patients with primary aldosteronism, age, BMI, and a higher number of antihypertensive drugs (lowest tertile vs. highest tertile) were variables associated with diabetes mellitus. In contrast, serum potassium and plasma aldosterone concentrations were not associated with higher diabetes prevalence, whereas diastolic blood pressure was inversely associated with diabetes mellitus. Diabetes mellitus was more prevalent in patients with PA than in 338 matched controls (23 vs. 10% in controls). Our data for the German population show that diabetes mellitus is more prevalent in patients with primary aldosteronism than in hypertensive controls.
PDF
