High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7).

The aim of this study was to determine whether glutamic acid decarboxylase antibody (GADA) titer and other clinical parameters could define the risk of progression to insulin therapy in latent autoimmune diabetes in adults (LADA) patients during a 7-year follow-up. This study involved 220 LADA and 430 type 2 diabetes subjects followed up for 7 years from the time of GADA screening to evaluate their progression toward insulin therapy. Kaplan-Meier curves and multivariate logistic regression analysis were performed to identify the markers capable of influencing this progression. RESULTS: During the follow-up, the drop out was 4% in both groups. A total of 119 (56.1%) out of 212 LADA patients required insulin during the 7 years of follow-up. The Kaplan-Meier plots showed that 74/104 (71.1%) of high GADA titer required insulin compared with 45/108 (41.6%) of low GADA titer and with 86/412 (20.9%) of type 2 diabetes (P<0.0001 for both). A BMI of ???25???kg/m2 and IA-2IC and zinc transporter 8 (ZnT8) positivity were also shown as the markers of faster progression (P<0.0001 for both). The proportion of LADA patients requiring insulin was significantly higher in the group of subjects treated also with sulfonylurea in the first year from diagnosis compared with those treated with diet and/or insulin sensitizers (P<0.001). The multivariate analysis confirmed that the presence of high GADA titer was a significant predictor of insulin requirement (P<0.0001, OR=6.95). CONCLUSIONS: High GADA titer, BMI ??? 25, ZnT8 and IA-2IC positivity and sulfonylurea treatment, in the first year from diagnosis, significantly increase the progression toward insulin requirement in LADA patients

The renal resistive index is associated with microvascular remodeling in patients with severe obesity

BACKGROUND Renal hemodynamics is impaired since the early stage of cardiometabolic disease. However, in obesity, its noninvasive ultrasound assessment still fails to provide pathophysiologic and clinical meaningfulness. We aimed to explore the relationship between peripheral microcirculation and renal hemodynamics in severe obesity. METHODS We enrolled fifty severely obese patients with an indication for bariatric referring to our outpatient clinic. Patients underwent an extensive reno-metabolic examination, paired with Doppler ultrasound and measurement of the renal resistive index (RRI). On the day of the surgery, visceral fat biopsies were collected to perform an ex-vivo complete microcirculatory assessment. Media-to-lumen ratio (M/L) and vascular response to acetylcholine (ACh), alone or co-incubated with N G -nitro arginine methyl ester (L-NAME), were measured. RESULTS Patients were stratified according to their normotensive (NT) or hypertensive (HT) status. HT had lower estimated glomerular filtration rate and higher RRI compared to NT, while the presence and extent of albuminuria were similar between the two groups. Concerning microcirculatory assessment, there were no differences between groups as regards the microvascular structure, while the vasorelaxation to ACh was lower in HT ( P = 0.042). Multivariable analysis showed a relationship between M/L and RRI ( P  = 0.016, St. β 0.37) and between albuminuria and the inhibitory response of L-NAME to Ach vasodilation ( P   =  0.036, St. β = -0.34). Notably, all these correlations were consistent also after adjustment for confounding factors. CONCLUSIONS The RRI and albuminuria relationship with microvascular remodeling in patients affected by severe obesity supports the clinical implementation of RRI to improve risk stratification in obesity and suggests a tight pathophysiologic connection between renal haemodynamics and microcirculatory disruption

The Beneficial Effects of Bariatric-Surgery-Induced Weight Loss on Renal Function

Obesity represents an independent risk factor for the development of chronic kidney disease (CKD), leading to specific histopathological alterations, known as obesity-related glomerulopathy. Bariatric surgery is the most effective means of inducing and maintaining sustained weight loss. Furthermore, in the context of bariatric-surgery-induced weight loss, a reduction in the proinflammatory state and an improvement in the adipokine profile occur, which may also contribute to the improvement of renal function following bariatric surgery. However, the assessment of renal function in the context of obesity and following marked weight loss is difficult, since the formulas adopted to estimate glomerular function use biomarkers whose production is dependent on muscle mass (creatinine) or adipose tissue mass and inflammation (cystatin-c). Thus, following bariatric surgery, the extent to which reductions in plasma concentrations reflect the actual improvement in renal function is not clear. Despite this limitation, the available literature suggests that in patients with hyperfiltration at baseline, GFR is reduced following bariatric surgery, whereas GFR is increased in patients with decreased GFR at baseline. These findings are also confirmed in the few studies that have used measured rather than estimated GFR. Albuminuria is also decreased following bariatric surgery. Moreover, bariatric surgery seems superior in achieving the remission of albuminuria and early CKD than the best medical treatment. In this article, we discuss the pathophysiology of renal complications in obesity, review the mechanisms through which weight loss induces improvements in renal function, and provide an overview of the renal outcomes following bariatric surgery

Long-term effects of bariatric surgery on meal disposal and beta-cell function in diabetic and nondiabetic patients.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes; the impact on glucose fluxes in response to a physiological stimulus - such as a mixed meal (MTT) - has not been determined. We administered an MTT to 12 obese type 2 diabetic patients (T2D) and 15 obese nondiabetic subjects (ND) before and one year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of ß-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels; peripheral insulin sensitivity increased in proportion to weight loss (∼30%), ß-cell glucose sensitivity doubled but did not normalize (viz. 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels.We conclude that, in type 2 diabetes bypass surgery changes the postprandial response to a dumping-like pattern, improves glucose tolerance, ß-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus

Mode of onset of type 2 diabetes from normal or impaired glucose tolerance

Wartości stężenia glukozy na czczo (FPG, fasting plasma glucose) wskazują, jakie jest ryzyko wystąpienia cukrzycy typu 2. Nie wiadomo, czy hiperglikemia rozwija się stopniowo, czy też narasta skokowo. W grupie mężczyzn i nieciężarnych kobiet w wieku 35&#8211;64 lat, biorących udział w badaniu populacyjnym Mexico City Diabetes Study, podczas doustnego testu tolerancji glukozy (OGTT, oral glucose tolerace test) sprawdzano stężenie glukozy i insuliny w surowicy. Testy te przeprowadzono w czasie badania wstępnego (n = 2279) oraz po 3,25 (n = 1740) i 7 latach (n = 1711) obserwacji. Wśród osób z prawidłową tolerancją glukozy (NGT, normal glucose tolerance) w czasie wszystkich trzech badań (osoby niechorujące, n = 911) wartość FPG wzrosła nieznacznie (0,23 &plusmn; 0,79 mmol/l, średnia &plusmn; SD; p < 0,0001) w okresie 7 lat. Natomiast wystąpienie cukrzycy wśród osób z NGT (n = 98) poprzedzał znaczny wzrost FPG, niezależnie od czasu zachorowania (3,06 &plusmn; 2,57 i 2,94 &plusmn; 3,11 mmol/l, odpowiednio w 3,25. i 7. roku obserwacji; p < 0,0001 vs. osoby niechorujące). Podobnie u osób z upośledzoną tolerancją glukozy, które zachorowały na cukrzycę (n = 75), wartość FPG wzrosła o 3,14 &plusmn; 3,83 i 3,12 &plusmn; 3,61 mmol/l (p < 0,0001 vs. osoby niechorujące). U 3/4 osób, które zachorowały na cukrzycę, obserwowano wzrost FPG powyżej 90. percentyla rozkładu wzrostu glikemii u osób niechorujących na cukrzycę. U osób, które zachorowały na cukrzycę, stwierdzono wyższe wyjściowe wartości wskaźnika masy ciała (BMI, body mass index) (30,4 &plusmn; 4,9 vs. 27,3 &plusmn; 4,0 kg/m2; p < 0,001) i insulinemii na czczo (120 &plusmn; 78 vs. 84 &plusmn; 84 pmol/l; p < 0,02) niż u osób niechorujących, mimo że nie zaobserwowano zmian żadnego z tych parametrów przed zachorowaniem. Przeciwnie, zmiany stężenia insuliny, w stosunku do wcześniejszych oznaczeń, w 2. godzinie testu tolerancji glukozy wykazywały istotną statystycznie odwrotną zależność (p < 0,0001) z odpowiadającymi zmianami w FPG. W czasie 3-letniej obserwacji stwierdzono, iż początek cukrzycy charakteryzuje się częściej skokowym niż stopniowym wzrostem glikemii, co można w pewnym stopniu wyjaśnić zmniejszeniem uwalniania insuliny w odpowiedzi na stymulację glukozą.Fasting plasma glucose concentrations (FPG) predict development of type 2 diabetes. Whether hyperglycemia evolves from normoglycemia gradually over time or as a step increase is not known. We measured plasma glucose and insulin levels during oral glucose testing in 35-to 64-year-old men and nonpregnant women from a population-based survey (Mexico City Diabetes Study) at baseline (n = 2,279) and after 3.25 (n = 1,740) and 7 years (n = 1,711) of follow-up. In subjects with normal glucose tolerance (NGT) on all three occasions (nonconverters; n = 911), FPG increased only slightly (0.23 &#177; 0.79 mmol/l, mean &#177; &#177; SD; P < 0.0001) over 7 years. In contrast, conversion to diabetes among NGT subjects (n = 98) was marked by a large step-up in FPG regardless of time of conversion (3.06 &#177; 2.57 and 2.94 &#177; 3.11 mmol/l, respectively, at 3.25 and 7 years; P < 0.0001 vs. nonconverters). Likewise, in subjects who converted to diabetes from impaired glucose tolerance (n = 75), FPG rose by 3.14 &#177; 3.83 and 3.12 &#177; 3.61 mmol/l (P < 0.0001 vs. nonconverters). Three-quarters of converters had increments in FPG above the 90th percentile of the corresponding increments in nonconverters. Converters had higher baseline BMI (30.4 &#177; &#177; 4.9 vs. 27.3 &#177; 4.0 kg/m2; P < 0.001) and fasting plasma insulin values (120 &#177; 78 vs. 84 &#177; 84 pmol/l; P < 0.02) than nonconverters; however, no consistent change in either parameter had occurred before conversion. In contrast, changes in 2-h postglucose insulin levels between time of conversion and preceding measurement were significantly (P < < 0.0001) related to the corresponding changes in FPG in an inverse manner. We conclude that, within a 3-year time frame, the onset of diabetes is very often rapid rather than gradual and is in part explained by a fall in glucose-stimulated insulin response

α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population

Background: Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects. Methods: Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively). Results: Random forest statistical analysis selected alpha-hydroxybutyrate (alpha-HB) as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived M(FFM) = 33 [12] mu mol.min(-1).kg(FFM)(-1), median [interquartile range], n = 140) from insulin sensitive subjects (M(FFM) = 66 [23] mu mol.min(-1).kg(FFM)(-1)) with a 76% accuracy. By targeted isotope dilution assay, plasma alpha-HB concentrations were reciprocally related to M(FFM); and by partition analysis, an alpha-HB value of 5 mu g/ml was found to best separate insulin resistant from insulin sensitive subjects. alpha-HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to alpha-HB metabolism and biosynthesis. Conclusions: alpha-hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress

Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

ackground: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. Methods: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. Results: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. Conclusions: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction. Keywords: aging; endothelial cells; microcirculation; mitochondria; obesity; sirtuin

Reply to Landry et al. Findings from Diet Comparison Difficult to Interpret in the Absence of Adherence Assessment. Comment on “Tricò et al. Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and β-Cell Function in Morbidly Obese Individuals. Nutrients 2021, 13, 1345”

We thank Dr. Landry and colleagues [...