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Aims: Since it is unknown whether glucose variability (GV) is increased and whether this is related to worsening of insulin secretion and action in prediabetes, we have assessed insulin secretion and sensitivity, and daily GV in early stages of dysglycemia., Materials and Methods: Twenty subjects with normal glucose tolerance (NGT; age 45.0 ± 9.5 years; BMI 31.1 ± 6.4 kg/m2), 25 with NGT and 1hrOGTT>8.6 mmol/L (1hrOGTT; 45.7 ± 8.5 years; 32.4 ± 7.0 kg/m2), and 59 with isolated impaired glucose tolerance (iIGT; 47.7 ± 11.2 years; 31.3 ± 6.1 kg/m2) underwent OGTT and MMTT. CGM was performed with blinded FreeStyle Libre Pro for 24 h under standard conditions. Parameters of beta-cell function, insulin sensitivity and GV were calculated., Results: Overall insulin secretion and action as well as GV progressively worsened across glucose tolerance categories. On a matrix analysis, GV parameters were inversely related to ISSI-2; r = -0.37 to -0.52; p < 0.0001; and IGI; r = -0.28 to -0.48; p < 0.0001 for CV, SD, J-index, LI, HBGI and MAGE. Insulin secretion (IGI) and b-cell function (ISSI-2) emerged as independent contributors to GV in early stage of dysglycemia accounting for about 16%-38% of its variability., Conclusions: Our results show that daily GV worsens already with mild impairment of glucose tolerance. The increase in GV is inversely related to insulin secretion and action., (© 2022 John Wiley & Sons Ltd.)

Aim: MG53 is a myokine modulating insulin signaling in several tissues; its relationship to glucose tolerance or risk of developing type 2 diabetes mellitus (T2DM) is unknown. This observational, prospective study aimed at evaluating the relationship between MG53 and glucose tolerance, testing whether its circulating levels may be associated with disease progression in a cohort at high risk of T2DM., Methods: Five hundred and fifteen subjects who underwent a deep characterization of their glucose tolerance in the years 2003-2005 participated in this study. MG53 levels were measured at baseline. Glucose tolerance status was available over a follow-up of 15 ± 2 years for 283 of them; their vital status as of December 2020 was also retrieved., Results: MG53 levels were significantly lower in subjects with normal glucose tolerance than in subjects with impaired glucose regulation (IGR) or T2DM. Individuals in the highest MG53 levels quartile had more frequently 1h-post load glucose ≥ 155 mg/dL (54% vs 39%; p = 0.015), worse proportional control of β-cell function (p < 0.05-0.01), as determined by mathematical modeling, and worse Disposition Index (DI) (0.0155 ± 0.0081 vs 0.0277 ± 0.0030; p < 0.0001). At follow-up, baseline MG53 levels were higher in progressors than in non-progressors (120.1 ± 76.7 vs 72.7 ± 63.2 pg/ml; p = 0.001; ROC curve area for incident diabetes of 0.704). In a multivariable regression with classic risk factors for T2DM and DI, MG53 remained independently associated with progression with T2DM., Conclusion: MG53 may be a novel biomarker of glucose dysregulation associated with β-cell dysfunction, likely improving our ability to identify, among high-risk subjects, those more likely to develop T2DM., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Aim: To investigate the effect of sitagliptin (SITA) and metformin (MET) monotherapy as well as in combination (MET+SITA) on beta-cell function and insulin sensitivity in women with recent gestational diabetes (GDM) and impaired glucose regulation (IGR: impaired fasting glucose and/or impaired glucose tolerance)., Material and Methods: Forty women were randomly assigned to receive SITA (100 mg qd), MET (850 mg bid) or MET+SITA (50 + 850 mg bid) for 16 weeks. A 75 g oral glucose tolerance test (OGTT) and +125 mg/dL hyperglycaemic clamp followed by 5 g i.v. L-arginine were performed at baseline and end of study. The primary outcome of the study was the mean change in arginine-stimulated insulin secretion rate during the hyperglycaemic clamp test from baseline to 16-week therapy., Results: At week 16, body mass index declined in all groups (-1.2 ± 0.2 kg/m 2 ; P < 0.05). MET+SITA gave a greater increase of first phase (2-10 min) insulin secretion and arginine-stimulated response (720.3 ± 299.0 to 995.5 ± 370.3 pmol/L and 3.2 ± 0.6 to 4.8 ± 1.0 pmoL/min, respectively, both P < 0.05) compared with MET and SITA. Similarly, MET+SITA was more effective in increasing OGTT-based glucose sensitivity (55.7 ± 11.3 to 108 ± 56.2 pmol x min -1 m -2 x mM -1 ; P = 0.04) and insulin-stimulated glucose disposal (M/I: 2.2 ± 0.5 to 4.6 ± 1.3 mg/kg/min÷μIU/min/ml; P = 0.04; Matsuda index [SI]: 3.1 ± 0.4 to 5.7 ± 1.1; P = 0.03) compared with either MET or SITA. Disposition index (ISSI-2) increased with MET+SITA and SITA (both P < 0.05), while no significant change was observed in MET. Among MET+SITA women, 33% reverted to normal glucose tolerance (NGT) compared with 14% with MET and 7% with SITA (P < 0.05)., Conclusion: This study shows that MET+SITA is superior to SITA and MET monotherapy regarding beta-cell function and insulin sensitivity improvement in IGR women with previous GDM, and may offer a potential pharmacologic intervention to reduce the risk of type 2 diabetes in this high-risk population., (© 2019 John Wiley & Sons Ltd.)

Context: In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test [OGTT]) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with subclinical atherosclerosis., Objective: The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL., Patients and Methods: The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well., Results: A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function., Conclusions: Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.

Type 2 diabetes is a chronic disease characterized by progressive worsening of glycaemic control as indicated by the United Kingdom Prospective Diabetes Study (UKPDS). The progressive nature of the disease is mainly due to continuous loss of beta-cell mass and function. Though much of this loss is due to intrinsic defects of the beta-cell several factors may accelerate such process. These include the metabolic environment where hyperglycaemia and increased circulating free-fatty acid exert a toxic effect on the beta-cell. Therefore, tight metabolic control may prevent not only the risk of long-term diabetic complication but also preserve beta-cell function. Several therapeutic agents are currently used for treatment of type 2 diabetic patients. However, their effect on maintenance of beta-cell function has not been yet systematically reviewed. By literature searching we have then analysed in detail the effect of sulfonylureas and non-sulfonylureic secretagogues, incretin-mimetics, insulin sensitizers, alpha-glucosidase inhibitors, and insulin on beta-cell function. Moreover, promising future approaches aiming at preserving beta-cell function and mass are discussed., ((c) 2007 John Wiley & Sons, Ltd.)

OBJECTIVE-To ascertain to which extent the use of HbA1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile. RESEARCH DESIGN AND METHOD-A total of 844 subjects (44%men; age 49.5±11 years; BMI 29±5 kg/m2) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasismodel assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile. RESULT-OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had aworse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion. CONCLUSION-HbA1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile. [ABSTRACT FROM AUTHOR]

The dyslipidemia of insulin resistance is characterized by elevated levels of triglycerides (TGs), low HDL-cholesterol and small dense LDL particles. Many of these features are affected by the reduction in insulin sensitivity, with a central role played by abnormalities in assembly and secretion of VLDL. Postprandial hyperlipidemia is common in insulin-resistant individuals, probably owing to reduced lipolysis of nascent chylomicrons. Increased exchange of HDL cholesteryl esters for TGs is associated with lipolysis of HDL-TG by hepatic lipase and this produces dysfuntional particles that are less stable than normal particles and contribute to decreased reverse cholesterol transport. On the other hand, TG accumulation has been described as dangerous for several tissues, the so-called lipotoxicity, particularly for pancreatic β-cells where it results in impairment of glucose-stimulated insulin secretion and accelerated apoptosis. Recently, islet dysfunction and loss of insulin secretion have also been associated with alterations of plasma and islet cholesterol levels. A more comprehensive appreciation of reciprocal effects of insulin resistance and atherogenic dyslipidemia should guide the physician in a more conscious therapeutic decision. [ABSTRACT FROM AUTHOR]

The metabolic syndrome (MS), a cluster of metabolic abnormalities with insulin resistance as its central component, is increasing in prevalence and is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus (T2DM). Current evidence supports an aggressive intervention approach that comprises lifestyle modification in conjunction with drug treatment of the MS components. Healthier eating and regular exercise greatly reduce waistline and body mass index, lower blood pressure and improve lipid profile. Lifestyle modification has been proven to prevent T2DM development. Nevertheless, appropriate treatment of MS components often requires pharmacologic intervention with insulin-sensitizing agents, such as metformin and thiazolidinediones, while statins and fibrates, or angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are the first-line lipid-modifying or antihypertensive drugs. Only severely obese patients require specific drug treatments. Very often, drug combinations will be necessary to manage multiple risk factors. As we progress in the understanding of the pathophysiology of the MS, new targets for therapies will probably be identified and new treatments will prove to be even more efficacious than those currently available for the management of this life-threatening condition. [ABSTRACT FROM AUTHOR]

Summary: Background and aim: To evaluate the prevalence of the metabolic syndrome as defined by NCEP ATP III criteria in an Italian cohort of adult subjects. Methods and results: A total of 2100 subjects aged 19 years or more, were randomly selected from the general population of the Lucca area. Metabolic syndrome was defined by the clustering of three or more of the following abnormalities: waist circumference greater than 102 cm in men and 88 cm in women; serum triglycerides level of at least 150 mg/dl (1.69 mmol/l); high-density lipoprotein cholesterol less than 40 mg/dl (1.04 mmol/l) in men and 50 mg/dl (1.29 mmol/l) in women; blood pressure greater than 130/85 mmHg; or serum glucose greater than 110 mg/dl (6.1 mmol/l). The prevalence of the metabolic syndrome was 18% in women and 15% in men. The prevalence increased from 3% among subjects aged 20–29 years to 25% in subjects aged 70 years or older. Application of this estimated prevalence data to the Italian adult population suggests that 3.6 million women and 3 million men may have the metabolic syndrome. Conclusions: The prevalence of metabolic syndrome in a cohort likely representative of the Italian adult population is high. The recognition of the syndrome may represent an important challenge for physicians and healthcare and requires immediate strategies aimed to reduce level of individual metabolic traits. [Copyright &y& Elsevier]

• A 1-hour plasma glucose (1-h PG) ≥ 155 mg/dl (8.6 mmol/L) during an oral glucose tolerance test (OGTT) can identify normal glucose tolerant (NGT) individuals at high-risk for type 2 diabetes (T2D). • A 1-hour, non-fasting, 50 g Glucose Challenge Test (GCT) performed during a routine health care visit has potential for practical screening of glucose disorders. • The shape of the glucose curve reflects the cumulative effect of insulin sensitivity and response on glucose concentrations with prospective studies warranted to evaluate its prognostic utility. • The continuous glucose monitor (CGM) has facilitated insight into the pathophysiology of prediabetes and phenotypes of T2D and holds promise for detecting glycemic disorders. • Metabolomic profiling including amino acids, lipids, carbohydrates and other metabolites may be useful for early diagnosis of glycemic disorders. • Non-classical markers for assessing glycemic disorders including fructosamine, glycated albumin, and 1,5-anhydroglucitol that evaluate shorter periods of glucose exposure than HbA1c have potential use as adjunctive tools. Prediabetes (intermediate hyperglycemia) consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) detected by a standardized 75-gram oral glucose tolerance test (OGTT). Individuals with isolated IGT or combined IFG and IGT have increased risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Diagnosing prediabetes early and accurately is critical in order to refer high-risk individuals for intensive lifestyle modification. However, there is currently no international consensus for diagnosing prediabetes with HbA1c or glucose measurements based upon American Diabetes Association (ADA) and the World Health Organization (WHO) criteria that identify different populations at risk for progressing to diabetes. Various caveats affecting the accuracy of interpreting the HbA1c including genetics complicate this further. This review describes established methods for detecting glucose disorders based upon glucose and HbA1c parameters as well as novel approaches including the 1-hour plasma glucose (1-h PG), glucose challenge test (GCT), shape of the glucose curve, genetics, continuous glucose monitoring (CGM), measures of insulin secretion and sensitivity, metabolomics, and ancillary tools such as fructosamine, glycated albumin (GA), 1,5- anhydroglucitol (1,5-AG). Of the approaches considered, the 1-h PG has considerable potential as a biomarker for detecting glucose disorders if confirmed by additional data including health economic analysis. Whether the 1-h OGTT is superior to genetics and omics in providing greater precision for individualized treatment requires further investigation. These methods will need to demonstrate substantially superiority to simpler tools for detecting glucose disorders to justify their cost and complexity. [ABSTRACT FROM AUTHOR]