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Purpose We aimed to clarify the onset of diabetes. Methods Data from 27,392 non-diabetic health examinees was retrospectively analyzed for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index (BMI) and the single point insulin sensitivity estimator (SPISE), an index of insulin sensitivity (Si), 10 years prior to diagn...

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... In particular, the risk factors for type 2 diabetes and their contributions in the initial phases of the disease remain uncertain [1,[3][4][5][6][7][8][9][10][11]. Specifically, the trajectory of plasma glucose level before clinical diagnosis of diabetes and prediabetes reveal that a stable, long-lasting, slow elevation is followed by an accelerated rise for several years before the diagnosis [7,[12][13][14][15]. This so-called multistage model strongly suggests unfavorable interactions between minimally elevated glucose per se and the glucose regulatory mechanism. ...
... In Caucasians and Pima Indians, insulin resistance that evolves during the development of type 2 diabetes induces insulin hypersecretion and increased insulin synthesis [1,[4][5][6]. However, such compensatory hyperinsulinemia during the development of type 2 diabetes has not been shown in Japanese people who are generally nonobese and insulin-sensitive [3,[8][9][10][11][12]. ...
... In a sense, the issue is semantics regarding "what is the normal range?" If we permit the inclusion of people with the possibility of developing diabetes or prediabetes in the future [7,11,12] as "normal," the upper limit of "the normal range" naturally goes up. However, if we completely exclude such people from the normal, the upper limit of "the normal range" goes down. ...
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Objective To clarify the impact of hepatic steatosis (HS) indexed by Fatty Liver Index (FLI) and high normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a non-obese cohort. Methods Data from 1,125 participants with ADA-defined normal glucose metabolism (NGM) (median age and BMI, 52 years and 23.1 kg/m 2, respectively) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression with adjustment for age and sex. Follow-up data from 599 participants in whom 75 g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model. Results In the entire population, FLI was positively correlated with FPG (P <0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2,061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISIMATSUDA and Stumvoll-1, clarified an increased risk of prediabetes with high normal FPG and FLI. In in participants with FLI≥16.5, as compared with FLI <16.5, P<0.001. The risk was also increased (2.1 times) in participants with FPG ≥5.3 mmol/L, P<0.001. The cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden’s index using the entire range of the variables. Conclusions Even among non-obese individuals, HS indexed by FLI and a high-normal FPG (≥5.3 mmol/L) are risk factors for prediabetes, independently from insulin.
... Moreover, it has been reported that higher fasting plasma glucose levels can be observed at least 10 years before the diagnosis of T2DM. 191 Although migraine has been associated with some factors implicated in diabetes, such as obesity and insulin resistance, to date little is known about the relationship between migraine and T2DM. Interestingly, Fagherazzi et al. recently reported 59 a linear decrease in the prevalence of migraine during the 24 years prior to T2DM diagnosis. ...
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Increasing evidence suggests that migraine may be the result of an impaired brain glucose metabolism. Several studies have reported brain mitochondrial dysfunction, impaired brain glucose metabolism and gray matter volume reduction in specific brain areas of migraineurs. Furthermore, peripheral insulin resistance, a condition demonstrated in several studies, may extend to the brain, leading to brain insulin resistance. This condition has been proven to downregulate insulin receptors, both in astrocytes and neurons, triggering a reduction in glucose uptake and glycogen synthesis, mainly during high metabolic demand. This scoping review examines the clinical, epidemiologic and pathophysiologic data supporting the hypothesis that abnormalities in brain glucose metabolism may generate a mismatch between the brain's energy reserve and metabolic expenditure, triggering migraine attacks. Moreover, alteration in glucose homeostasis could generate a chronic brain energy deficit promoting migraine chronification. Lastly, insulin resistance may link migraine with its comorbidities, like obesity, depression, cognitive impairment and cerebrovascular diseases. Perspective: Although additional experimental studies are needed to support this novel “neuroenergetic” hypothesis, brain insulin resistance in migraineurs may unravel the pathophysiological mechanisms of the disease, explaining the migraine chronification and connecting migraine with comorbidities. Therefore, this hypothesis could elucidate novel potential approaches for migraine treatment.
... reported that glucose dysregulation precedes the actual diagnosis of T2D by >10 years (45) in adults, while Lebovitz et al. reported that b-cell dysfunction in adults precedes clinical diagnosis of T2D by 12 years (46). In contrast, the diagnosis of T1D is often followed by the honeymoon phase or PR which largely determines the risks for early-phase dyslipidemia (6), mid-term microvascular disease risk (7), and long-term CVD risk (8). ...
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Literature Search Criteria A literature search was conducted to identify publications addressing the early phases of lipid phenotypes in children and adults with either type 1 diabetes or type 2 diabetes. Medline, EMBASE, and Ovid were searched using the following search terms: clinical remission, partial remission, partial clinical remission, honeymoon phase, C-peptide, type 1 or 2 diabetes, children, pediatric type 1 or 2 diabetes, and paediatrics type 1 or 2 diabetes, adults, adult type 1 or type 2 diabetes. Partial clinical remission (PR) of type 1 diabetes (T1D) is characterized by continued endogenous production of insulin and C-peptide following the diagnosis and the introduction of exogenous insulin therapy. PR is associated with improved glycemic control and reduced prevalence of diabetes complications. The theory of hyperglycemic memory was proposed to explain this concept of improved glycemic outcomes in remitters (those who experienced PR) versus non-remitters (those who did not experience PR). However, this theory is incomplete as it does not explain the dichotomy in early lipid phenotypes in T1D based on PR status, which is an understudied area in diabetology and lipidology. To fill this knowledge gap, we propose the Theory of Hyperlipidemic Memory of T1D. This theory is premised on our 5-year research on early post-diagnostic dichotomy in lipid phenotypes between remitters and non-remitters across the lifespan. It provides a more rigorous explanation for the differences in lifelong atherosclerotic cardiovascular disease (ASCVD) risk between remitters and non-remitters. We conducted 4 clinical studies in pediatric and adult subjects with diabetes mellitus to characterize the particulars of the hyperlipidemic memory. In the first investigation, we explored the impact of the presence or absence of PR on lipid parameters in children and adolescents with T1D. In the second, we investigated whether pubertal maturation influenced our findings in T1D; and whether these findings could be replicated in healthy, non-diabetic children and adolescents. In the third, we leveraged our findings from T1D and controls to investigate the mechanisms of early lipid changes in T2D by comparing the earliest lipid phenotype of subjects with type 2 diabetes (T2D) to those of remitters, non-remitters, and controls. In the fourth, we investigated the impact of PR on the earliest lipid phenotypes in adults with T1D and compared these early lipid data to those of T2D subjects and controls. This body of work across the lifespan in children, adolescents, and adults supports the Theory of Hyperlipidemic Memory. This new theory clarifies why PR largely determines the risks for early-phase dyslipidemia, mid-term microvascular disease risk, and long-term ASCVD risk in subjects with T1D.
... Among these, the SPISE was developed as an easy and affordable tool for the evaluation of whole-body insulin sensitivity, which is comparable to clamp-derived M-value in sensitivity as well as specificity (19). Several studies have evaluated the SPISE in adult as well as juvenile populations (20,(41)(42)(43)(44)(45)(46). Correa-Burrows et al. assessed SPISE for its validity in diagnosing cardiometabolic risks, namely IR and metabolic syndrome, in post-pubertal Hispanic adolescents. ...
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Background Attenuated insulin-sensitivity (IS) is a central feature of pediatric non-alcoholic fatty liver disease (NAFLD). We recently developed a new index, single point insulin sensitivity estimator (SPISE), based on triglycerides, high-density-lipoprotein and body-mass-index (BMI), and validated by euglycemic-hyperinsulinemic clamp-test (EHCT) in adolescents. This study aims to assess the performance of SPISE as an estimation of hepatic insulin (in-)sensitivity. Our results introduce SPISE as a novel and inexpensive index of hepatic insulin resistance, superior to established indices in children and adolescents with obesity. Materials and Methods Ninety-nine pubertal subjects with obesity (13.5 ± 2.0 years, 59.6% males, overall mean BMI-SDS + 2.8 ± 0.6) were stratified by MRI (magnetic resonance imaging) into a NAFLD (>5% liver-fat-content; male n=41, female n=16) and non-NAFLD (≤5%; male n=18, female n=24) group. Obesity was defined according to WHO criteria (> 2 BMI-SDS). EHCT were used to determine IS in a subgroup (n=17). Receiver-operating-characteristic (ROC)-curve was performed for diagnostic ability of SPISE, HOMA-IR (homeostatic model assessment for insulin resistance), and HIRI (hepatic insulin resistance index), assuming null hypothesis of no difference in area-under-the-curve (AUC) at 0.5. Results SPISE was lower in NAFLD (male: 4.8 ± 1.2, female: 4.5 ± 1.1) than in non-NAFLD group (male 6.0 ± 1.6, female 5.6 ± 1.5; P< 0.05 {95% confidence interval [CI]: male NAFLD 4.5, 5.2; male non-NAFLD 5.2, 6.8; female NAFLD 4.0, 5.1, female non-NAFLD 5.0, 6.2}). In males, ROC-AUC was 0.71 for SPISE (P=0.006, 95% CI: 0.54, 0.87), 0.68 for HOMA-IR (P=0.038, 95% CI: 0.48, 0.88), and 0.50 for HIRI (P=0.543, 95% CI: 0.27, 0.74). In females, ROC-AUC was 0.74 for SPISE (P=0.006), 0.59 for HOMA-IR (P=0.214), and 0.68 for HIRI (P=0.072). The optimal cutoff-level for SPISE between NAFLD and non-NAFLD patients was 5.18 overall (Youden-index: 0.35; sensitivity 0.68%, specificity 0.67%). Conclusion SPISE is significantly lower in juvenile patients with obesity-associated NAFLD. Our results suggest that SPISE indicates hepatic IR in pediatric NAFLD patients with sensitivity and specificity superior to established indices of hepatic IR.
... It precedes disease manifestation for up to 20 years and, therefore, is an early sign of metabolic dysfunction. 1 Thus, understanding insulin sensitivity remains important to improve T2DM prevention. Insulin sensitivity is mainly determined by a crosstalk between the liver, the adipose tissue, and skeletal muscle. 2 Skeletal muscle plays a particularly important role, because, in healthy individuals, it is responsible for approximately 80% of insulinstimulated whole-body glucose uptake and disposal. ...
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Introduction Skeletal muscle contributes significantly to insulin sensitivity in humans. However, which non-invasive measurement best reflects this contribution remains unknown. Consequently, this paper compares morphologic and functional measurements. Research methods and design We conducted a cross-sectional analysis of 144 premenopausal women enrolled in the “Prediction, Prevention, and Sub-classification of Type 2 Diabetes” (PPSDiab) cohort study. For the analysis, we quantified insulin sensitivity by oral glucose tolerance testing and, in a subgroup of 30 women, euglycemic clamp. To assess skeletal muscle, we measured volume by magnetic resonance imaging, intramyocellular lipid content by magnetic resonance spectroscopy, and physical fitness by cardiopulmonary exercise testing. Results The mean age of the cohort was 35.7 ± 4.1 years and 94 participants (65%) had a history of gestational diabetes mellitus. Of the morphologic and functional muscle parameters, the maximum workload achieved during cardiopulmonary exercise testing associated most closely with insulin sensitivity (standardized beta = 0.39; p < .001). Peak oxygen uptake also demonstrated significant associations, whereas muscle volume and intramyocellular lipid content displayed none. Conclusion Functional measurements provided a better assessment of the muscular contribution to insulin sensitivity than morphologic measurements in premenopausal women. In particular, exercise testing rendered an easy and cost-effective method applicable in clinical settings and other human studies.
... Thus, our results may not be widely generalizable to other settings or other new diabetes patients. However, we used 3 years cut-off to define newly diagnosed T2DM due to the long natural progression of T2DM [22,23] and the potential delay in receiving T2DM diagnosis among our study population, of which the majority came from lower socioeconomic levels [24,25]. Second, our study was designed to assess the association between LTBI and the risk of T2DM. ...
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Objective The purpose of this study is to compare the prevalence of latent TB infection (LTBI) among patients with type-2 diabetes mellitus (T2DM) to healthy controls without T2DM. To achieve this objective, we conducted a case-control study in a large hospital in Atlanta from 2016 to 2019. Results We enrolled 98 cases; 119 potential controls were screened, 84 of which had HbA1c ≥ 5.7% and one did not have QFT result, leaving 34 (28.6%) individuals enrolled as controls. LTBI prevalence was 9.2% among cases and 14.7% among controls (crude odds ratio 0.59, 95% CI 0.19–2.04). After adjusting for age and sex, the adjusted odds of LTBI among patients with T2DM was 0.45 (95% CI 0.13, 1.71) times the controls. We did not observe a statistically significant association between LTBI and T2DM. However, we reported a positive correlation between HbA1c level and nil count among individuals with LTBI (R ² = 0.55, p < 0.01). In addition, we reported a high prevalence of LTBI among adults with T2DM and family members without T2DM.
... Material, part 6) (15,23,75). For T1D, adult deaths from diabetic ketoacidosis, 800 in the U.S. in 2017, emphasize the importance of earlier diagnosis and prevention (76,77). ...
Article
As the world endures a viral pandemic superimposed on a diabetes pandemic, the latter incorporates most of the comorbidities associated with the former, thereby exacerbating risk of death in both. An essential approach to both pandemics is prevention and unrealized earlier treatment. Thus, in this Perspective relating to diabetes, we emphasize a paradigm of, first, reversible β-cell organ dysfunction and then irreversible β-cell organ failure, which directly indicate the potential for earlier prevention, also unrealized in current guidelines. Four pillars support this paradigm: epidemiology, pathophysiology, molecular pathology, and genetics. A substantial worldwide knowledge base defines each pillar and informs a more aggressive preventive approach to most forms of the disorder. This analysis seeks to clarify the temporal and therapeutic relationships between lost β-cell function and content, illuminating the potential for earlier diagnoses and, thus, prevention. We also propose that myriad pathways leading to most forms of diabetes converge at the endoplasmic reticulum, where stress can result in β-cell death and content loss. Finally, genetic and nongenetic origins common to major types of diabetes can inform earlier diagnosis and, potentially, prevention, with the aim of preserving β-cell mass.
... Current evidence suggests that constant positive energy balance in the modern obesogenic environment leads initially to hyperinsulinemia [31] in an effort to maintain normoglycemia. Indeed, it is known that insulin levels rise almost a decade before diabetes is detected [32][33][34][35] and are sometimes referred to as Stage 1 of diabetes associated with compensation [36]. ...
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Non-alcoholic fatty liver disease (NAFLD) is a fast-spreading epidemic across the globe and has serious implications far beyond that of a "benign" liver condition. It is usually an outcome of ectopic fat storage due to chronic positive energy balance leading to obesity and is associated with multiple health problems. While association with cardiovascular disease and hepatocellular cancer is well recognized, it is becoming clear the NAFLD carries with it an increased risk of cancers of extrahepatic tissues. Studies have reported a higher risk for cancers of the colon, breast, prostate, lung, and pancreas. Fatty liver is associated with increased mortality; there is an urgent need to understand that fatty liver is not always benign, and not always associated with obesity. It is, however, a reversible condition and early recognition and intervention can alter its natural history and associated complications.
... Moreover, lower SPISE index significantly correlated in adults or adolescents with the presence of T2D [36], metabolic syndrome [37,39], risk of cardiovascular diseases [36], non-alcoholic fatty liver disease (NAFLD) [38], abdominal obesity, higher levels of C-reactive protein (CRP) and lower levels of adiponectin [24]. Finally, in line with our results obtained in youths, Sagesaka et al. demonstrated that basal SPISE index was significantly lower in adults who developed T2D 10 years later in comparison to those who did not progress to diabetes, in a longitudinal investigation on over 27,000 individuals without diabetes [40]. ...
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Purpose To investigate the relationship between the single-point insulin sensitivity estimator (SPISE) index, an insulin sensitivity indicator validated in adolescents and adults, and metabolic profile in overweight/obese children, and to evaluate whether basal SPISE is predictive of impaired glucose regulation (IGR) development later in life. Methods The SPISE index (= 600 × HDL 0.185 /Triglycerides 0.2 × BMI 1.338 ) was calculated in 909 overweight/obese children undergoing metabolic evaluations at University of Cagliari, Italy, and in 99 normal-weight, age-, sex-comparable children, selected as a reference group, together with other insulin-derived indicators of insulin sensitivity/resistance. 200 overweight/obese children were followed-up for 6.5 [3.5–10] years, data were used for longitudinal retrospective investigations. Results At baseline, 96/909 (11%) overweight/obese children had IGR; in this subgroup, SPISE was significantly lower than in normo-glycaemic youths (6.3 ± 1.7 vs. 7 ± 1.6, p < 0.001). The SPISE index correlated positively with the insulin sensitivity index (ISI) and the disposition index (DI), negatively with age, blood pressure, HOMA-IR, basal and 120 min blood glucose and insulin (all p values < 0.001). A correlation between SPISE, HOMA-IR and ISI was also reported in normal-weight children. At the 6.5-year follow-up, lower basal SPISE—but not ISI or HOMA-IR—was an independent predictor of IGR development (OR = 3.89(1.65–9.13), p = 0.002; AUROC: 0.82(0.72–0.92), p < 0.001). Conclusion In children, low SPISE index is significantly associated with metabolic abnormalities and predicts the development of IGR in life.
... Despite the RDSN findings, the Diabetes Heart Study demonstrated that QTc interval predicted all-cause and cardiovascular disease mortality in participants with type 2 diabetes mellitus [53], confirming the results previously obtained by Ewing et al [50]. In addition, in 2010, Pop-Busui et al [54] evaluated the mortality risk in participants with CAN and reported that CAN participants had a twofold all-cause mortality risk compared to individuals without CAN. ...
... The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial demonstrated that participants with CAN had similar mortality rates when following both standard and intensive treatments for glycemic control, suggesting that severe glycemic control could promote hypoglycemia and increase the probability of mortality in diabetic patients [54]. Another study developed by Tang et al [51] based on the ACCORD trial evaluated the effects of intensive treatment of hyperglycemia, hypertension, and dyslipidemia as a prevention strategy to reduce cardiovascular events. ...
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Cardiovascular autonomic neuropathy (CAN) is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier, even before diabetes is diagnosed. CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers, which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control. The entire mechanism is still not elucidated, but several aspects of the pathophysiology of CAN have already been described, such as the production of advanced glycation end products, reactive oxygen species, nuclear factor kappa B, and pro-inflammatory cytokines. This microvascular complication is an important risk factor for silent myocardial ischemia, chronic kidney disease, myocardial dysfunction, major cardiovascular events, cardiac arrhythmias, and sudden death. It has also been suggested that, compared to other traditional cardiovascular risk factors, CAN progression may have a greater impact on cardiovascular disease development. However, CAN might be subclinical for several years, and a late diagnosis increases the mortality risk. The duration of the transition period from the subclinical to clinical stage remains unknown, but the progression of CAN is associated with a poor prognosis. Several tests can be used for CAN diagnosis, such as heart rate variability (HRV), cardiovascular autonomic reflex tests, and myocardial scintigraphy. Currently, it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV, which is a non-invasive test with a lower operating cost. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition. Key Words: Cardiovascular autonomic neuropathy, Cardiac autonomic neuropathy, Diabetes mellitus, Heart rate variability, Sympathetic autonomic nervous system, Parasympathetic autonomic nervous system