Hypothesis: ‘Vasocrine’ signalling from perivascular fat - a mechanism linking insulin resistance and vascular disease

Adipose tissue expresses cytokines which inhibit insulin signalling pathways in liver and muscle. Obesity also results in impairment of endothelium-dependent vasodilatation to insulin. We propose a vasoregulatory role for local deposits of fat around the origin of arterioles supplying skeletal muscle. Isolated first order arterioles from rat cremaster muscle are under dual regulation by insulin, which activates both endothelin-1 mediated vasoconstriction and nitric oxide mediated vasodilatation. In obese rat arterioles, insulin-stimulated nitric oxide synthesis is impaired, resulting in unopposed vasoconstriction. We propose this to be the consequence of production of the adipocytokine tumour necrosis factor-α from the cuff of fat seen surrounding the origin of the arteriole in obese rats – a depot to which we ascribe a specialist vasoregulatory role. We suggest that this cytokine accesses the nutritive vascular tree to inhibit insulin-mediated capillary recruitment – a mechanism we term ‘vasocrine’ signalling. We also suggest a homology between this vasoactive periarteriolar fat and both periarterial and visceral fat, which may explain relationships between visceral fat, insulin resistance and vascular disease

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations:a nation-wide cohort study

Background: Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods: A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results: Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion: SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect

Higher Plasma Soluble Receptor for Advanced Glycation End Products (sRAGE) Levels Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes: A 12-Year Follow-Up Study

To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and allcause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS - We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6 -12.5). RESULTS - The incidence of fatal and nonfatal CVD and allcause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13-3.21) and 2.12 (1.26 -3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91-2.77) for fatal and nonfatal CVD events and to 1.90 (1.09 -3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036). CONCLUSIONS - Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association

Combination of insulin and metformin in the treatment of type 2 diabetes

WSTĘP. Celem pracy była ocena działania metabolicznego metforminy w porównaniu z placebo, u chorych na cukrzycę typu 2, leczonych według schematu intensywnej insulinoterapii. MATERIAŁ I METODY. Metformina poprawia kontrolę glikemii u osób ze źle wyrównaną cukrzycą typu 2. Dotychczas nie zbadano jej wpływu u chorych na cukrzycę typu 2, leczonych metodą intensywnej insulinoterapii. Grupa 390 chorych na cukrzycę typu 2, stosujących insulinę, uczestniczyła w randomizowanym, kontrolowanym, przeprowadzonym metodą podwójnie ślepej próby badaniu z zaplanowaną pośrednią analizą po 16 tygodniach leczenia. Uczestników badania wybrano z 3 przyszpitalnych przychodni i losowo przydzielono do grup, przyjmujących placebo lub metforminę w uzupełnieniu insulinoterapii. Podczas badania prowadzono intensywną kontrolę glikemii z natychmiastowym dostosowaniem dawki insuliny, zgodnie ze ścisłymi wytycznymi. Określano wskaźniki kontroli glikemii, zapotrzebowanie na insulinę, masę ciała, ciśnienie tętnicze, stężenie lipidów, incydenty hipoglikemii i inne działania niepożądane. WYNIKI. Sposród 390 osób 37 nie ukończyło badania (12 w grupie otrzymującej placebo i 25 w grupie leczonej metforminą). U osób, które ukończyły 16-tygodniowy okres leczenia zastosowanie metforminy w porównaniu z placebo powodowało poprawę kontroli glikemii (średnia glikemia podczas 16 tygodni 7,8 vs. 8,8 mmol/l, p = 0,006; średnie stężenie HbA1c 6,9 vs. 7,6%, p < 0,0001), zmniejszone zapotrzebowanie na insulinę (63,8 vs. 71,3 j.; p < 0,0001), mniejszy przyrost masy ciała (-0,4 vs. +1,2 kg; p < 0,01) i zmniejszenie stężenia cholesterolu frakcji LDL (-0,21 vs. -0,02 mmol/l; p < 0,01). Ryzyko wystąpienia hipoglikemii było podobne. WNIOSKI. U chorych na cukrzycę typu 2, leczonych intensywnie insuliną, skojarzenie insuliny z metforminą powoduje lepsze wyrównanie glikemii w porównaniu z monoterapią insuliną, a jednocześnie zmniejsza zapotrzebowanie na insulinę i ogranicza przyrost masy ciała.INTRODUCTION. To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin. MATERIAL AND METHODS. Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured. RESULTS. Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P < 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P < 0.0001); reduced weight gain (&#8211;0.4 vs. +1.2 kg, P < 0.01); and decreased plasma LDL cholesterol (&#8211;0.21 vs. &#8211;0.02 mmol/l, P < 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS. In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less

Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.</p

Direct Classification of Type 2 Diabetes From Retinal Fundus Images in a Population-based Sample From The Maastricht Study

Type 2 Diabetes (T2D) is a chronic metabolic disorder that can lead to blindness and cardiovascular disease. Information about early stage T2D might be present in retinal fundus images, but to what extent these images can be used for a screening setting is still unknown. In this study, deep neural networks were employed to differentiate between fundus images from individuals with and without T2D. We investigated three methods to achieve high classification performance, measured by the area under the receiver operating curve (ROC-AUC). A multi-target learning approach to simultaneously output retinal biomarkers as well as T2D works best (AUC = 0.746 [$\pm$0.001]). Furthermore, the classification performance can be improved when images with high prediction uncertainty are referred to a specialist. We also show that the combination of images of the left and right eye per individual can further improve the classification performance (AUC = 0.758 [$\pm$0.003]), using a simple averaging approach. The results are promising, suggesting the feasibility of screening for T2D from retinal fundus images.Comment: to be published in the proceeding of SPIE - Medical Imaging 2020, 6 pages, 1 figur

Reduced corneal nerve fibre length in prediabetes and type 2 diabetes: The Maastricht Study

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Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: the REMOVAL trial

Aim: To determine whether metformin's effects on carotid artery intima‐media thickness (cIMT) in type 1 diabetes differ according to smoking status. Methods: Regression model effect estimates for the effect of metformin versus placebo (double‐blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. Results: In 428 randomized participants (227 never‐smokers, 201 ever‐smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.012 mm, 95% CI −0.021 to −0.002; p = .0137) but not in ever‐smokers (0.003 mm, 95% CI −0.008 to 0.014; p = .5767); and similarly in non‐current smokers (−0.008 mm, 95% CI −0.015 to −0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI −0.007 to 0.032; p = .1887). Three‐way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non‐current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never‐smokers (−0.020 mm, 95% CI −0.034 to −0.006; p = .0067) but not in ever‐smokers (−0.006 mm, 95% CI −0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three‐way interaction term. Conclusions: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes