The burden of type 2 diabetes is rapidly increasing in low- and middle-income countries (LMICs), but determinants are not well-characterized. Household air pollution (HAP) from indoor biofuel use for cooking has been associated with non-communicable diseases and could be contributing to the increasing burden of diabetes in LMICs, though data are limited. We assessed the association between indoor biofuel use for cooking and glucose metabolism in HIV-infected and HIV-uninfected Tanzanian adults. This cross-sectional analysis included Tanzanian adults with and without HIV, from whom we collected sociodemographic and non-communicable disease risk factor data. The main predictor variable was indoor biofuel use for cooking, established using self-reported cooking location (indoor or outdoor) and fuel type (electricity/gas or biomass fuel), and categorized as minimal or no exposure, moderate exposure, and high exposure. Blood glucose and insulin were measured during oral glucose tolerance tests, allowing computation of outcome variables including markers of β-cell dysfunction (homeostatic model assessment-β, insulinogenic index, oral disposition index), insulin resistance (HOMA-IR and Matsuda index), and pre-diabetes and diabetes status. Logistic regression was used to assess associations, adjusting for age, sex, physical activity, smoking, socioeconomic status, HIV status, and body mass index. Among 1,871 participants (mean age 40.6 ± 11.9 years; 59.8% female), those with moderate and high exposure to HAP had approximately two-fold higher odds of a lower insulinogenic index (adjusted odds ratio [aOR] = 2.13, 95% CI: 1.27-3.57 and aOR = 2.31, 95% CI: 1.39-3.83, respectively) compared to those with minimal or no exposure. HAP was not associated with other markers of β-cell function, insulin resistance, pre-diabetes, or diabetes. In conclusion, HAP is associated with increased risk of β-cell dysfunction among individuals using biofuel for indoor cooking. Longitudinal studies using objective HAP measurements are needed to confirm these findings.

Efficiently assessing glucose handling capacity is a critical public health challenge. This study assessed the utility of relatively easy-to-measure continuous glucose monitoring (CGM)-derived indices in estimating glucose handling capacities calculated from resource-intensive clamp tests.

We conducted a prospective study of 64 individuals without prior diabetes diagnosis. The study performed CGM, oral glucose tolerance tests (OGTT), and hyperglycemic and hyperinsulinemic-euglycemic clamp tests. We validated CGM-derived indices characteristics using an independent dataset from another country and mathematical models with simulated data.

A CGM-derived index reflecting the autocorrelation function of glucose levels (AC_Var) is significantly correlated with clamp-derived disposition index (DI), a well-established measure of glucose handling capacity and predictor of diabetes onset. Multivariate and machine learning models indicate AC_Var's contribution to predicting clamp-derived DI independent from other CGM-derived indices. The model using CGM-measured glucose standard deviation and AC_Var outperforms models using commonly used diabetes diagnostic indices, such as fasting blood glucose, HbA1c, and OGTT measures, in predicting clamp-derived DI. Mathematical simulations also demonstrate the association of AC_Var with DI.

CGM-derived indices, including AC_Var, serve as valuable tools for predicting glucose handling capacities in populations without prior diabetes diagnosis. We develop a web application that calculates these CGM-derived indices ( https://cgm-ac-mean-std.streamlit.app/ ).

Interleukin-6 (IL-6) knockout mice and humans treated with IL-6 receptor blockade gain adipose tissue mass. This study investigates whether basal IL-6 activity (resting IL-6 levels) influences fat storage during fasting and postprandial states. Using stable-isotope tracer techniques and IL-6 receptor blockade with tocilizumab, we examine fat kinetics in humans. Blocking basal IL-6 activity reduces fasting whole-body lipolysis, decreases hormone-sensitive lipase (HSL) phosphorylation and fatty acid release in adipose tissue, and impairs postprandial fatty acid uptake in the leg. These results suggest diminished fatty acid uptake and oxidation in skeletal muscle, along with enhanced fatty acid entrapment in adipose tissue, which may account for the increased adiposity in the absence of IL-6 activity. Additionally, IL-6 blockade increases the escape of meal-derived fatty acids into the bloodstream. Whether this affects fatty acid storage and lipotoxicity in other tissues warrants further investigation. This study was registered at ClinicalTrials.gov (NCT04687540).

People with later chronotypes are at greater T2D risk, yet it is unknown if β-cell function differs among chronotypes. Thus we, assessed β-cell function in morning (MORN) and intermediate (INT) chronotypes with obesity.

Adults (n = 41, 9M, 55 ± 1.7 y, 36.8 ± 1.0 kg/m2) were grouped as MORN or INT per the Morningness-Eveningness Questionnaire. Glucose, insulin, C-peptide, GIP, and GLP-1(active) were collected every 30 min during a 120 min 75g-OGTT. Insulin secretion rates (ISR) were calculated (regularized deconvolution) to assess early (total area under the curve; tAUC0-30min) and total-phase (tAUC0-120min) glucose-stimulated insulin secretion (GSIS:ISR/Glucose). Skeletal muscle (glucose infusion rate/steady-state insulin) insulin sensitivity and hepatic (HOMA-IR) as well as adipose (Adipose-IR) insulin resistance were assessed during a 120 min euglycemic hyperinsulinemic clamp (40mU/m2/min, 90 mg/dL). β-cell function (disposition index (DI): GSIS adjusted insulin sensitivity) was determined. Body composition (DXA) and fitness (VO2max) were also measured.

Age, body composition and VO2max were similar between groups, but INT had reduced muscle insulin sensitivity and higher hepatic and adipose IR (p < 0.05). INT had higher C-peptide tAUC0-30min (p = 0.04) and lower hepatic DI (tAUC0-30min p = 0.05 and tAUC0-120min p = 0.07, respectively). Early phase hepatic DI correlated with GLP-1 tAUC0-30min (r = 0.35, p < 0.02) and tAUC0-120min (r = -0.40, p = 0.04).

β-cell function was higher in MORN versus INT chronotypes. Further work is warranted to discern how chronotype impacts insulin secretion.

NCT03355469.

Roux-en-Y gastric bypass (RYGB) increases the risk of postprandial hypoglycemia, whereas pregnancy decreases insulin sensitivity, which could be expected to counteract hypoglycemia. We examined if RYGB performed prior to pregnancy altered the postprandial glucose metabolism and enteropancreatic hormone responses to a mixed meal test (MMT).

Twenty-three women with RYGB and 23 women matched on prepregnancy body mass index and parity underwent a 4-hour MMT in the first and third trimester of pregnancy with measurement of circulating levels of glucose, insulin, C-peptide, glucose-dependent insulin peptide (GIP), glucagon-like peptide 1 (GLP-1), glucagon, free fatty acids, and lactate. Biochemical hypoglycemia was defined as plasma glucose <3.5 mmol/L.

Women with RYGB had earlier and higher peak glucose, lower nadir glucose levels, and a higher frequency of biochemical hypoglycemia compared with women without RYGB in both the first and third trimester. The lower glucose levels were preceded by markedly elevated total GLP-1 and insulin levels in women with RYGB, whereas total GIP levels were unaltered. The glucagon levels were lower in women with RYGB. In the first trimester MMT, peak and area under the curve of total plasma GLP-1 and serum insulin levels were negatively associated with nadir plasma glucose, while the early postmeal response of plasma glucagon was positively associated with nadir plasma glucose in the third trimester.

These results provide novel insights into the combined effects of RYGB and pregnancy on postmeal glucose metabolism and enteropancreatic hormone responses during pregnancy, and how these changes associate with an increased risk of postprandial hypoglycemia.

NCT03713060.

To evaluate insulin secretion and insulin resistance profiles in individuals with family history of prediabetes and type 2 diabetes.

This was a cross-sectional study to evaluate clinical and metabolic profiles between individuals with type 2 diabetes, prediabetes and their relatives. There were 911 subjects divided into five groups: (i) normoglycemic (NG), (ii) type 2 diabetes, (iii) prediabetes, (iv) first-degree relatives of patients with type 2 diabetes (famT2D), and (v) first-degree relatives of patients with prediabetes (famPD); anthropometrical, biochemical and nutritional evaluation, as well as insulin resistance and pancreatic beta cell function measurement was performed by oral glucose tolerance to compare between groups.

The most prevalent type 2 diabetes risk factors were dyslipidemia (81%), family history of type 2 diabetes (76%), central obesity (73%), male sex (63%), and sedentary lifestyle (60%), and most of them were progressively associated to prediabetes and type 2 diabetes groups. Insulin sensitivity was lower in famT2D groups in comparison to NG group (p < 0.0001). FamPD and famT2D had a 10% lower pancreatic beta cell function (DI) than the NG group (NG group 2.78 ± 1.0, famPD 2.5 ± 0.85, famT2D 2.4 ± 0.75, p˂0.001).

FamPD and famT2D patients had lower pancreatic beta cell function than NG patients, highlighting that defects in insulin secretion and insulin sensitivity appear long time before the development of hyperglycemia in patients genetically predisposed.

Friedreich's ataxia (FRDA) is a multisystem disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM.

Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer magnetic resonance imaging) were assessed.

Participants included 11 individuals with FRDA (4 female), median age 27 years (interquartile range 23, 39), body mass index 26.9 kg/m2 (24.1, 29.4), and 24 controls (11 female), 29 years (26, 39), 24.4 kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA [91 vs 83 mg/dL (5.0 vs 4.6 mmol/L), P < .05]. Individuals with FRDA had lower insulin sensitivity (whole-body insulin sensitivity index 2.8 vs 5.3, P < .01), higher postprandial insulin secretion (insulin secretory rate incremental area under the curve 30-180 minutes, 24 652 vs 17,858, P < .05), and more suppressed postprandial endogenous glucose production (-.9% vs 26.9% of fasting endogenous glucose production, P < .05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different.

Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory and, when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.

This study aims to investigate the associations between MTNR1B rs724030 A>G variant and prediabetes risk, along with their correlations with clinical features, including plasma glucose and serum insulin levels during oral glucose tolerance test (OGTT), islet function, insulin resistance, and plasma lipid levels. In particular, we investigated whether there are sex dimorphisms in the impact of this variant on islet function/insulin resistance.

We included 3415 glucose-tolerant healthy and 1744 prediabetes individuals based on OGTT. Binary logistic regression was performed to evaluate the relationships between rs724030 in MTNR1B and prediabetes under the additive model. Additionally, multiple linear regression was utilized to investigate the associations between this variant and glycemic-related quantitative traits and lipid levels.

While no association was observed between the rs724030 variant in MTNR1B and prediabetes risk in the overall cohort (P > 0.05), we found the G allele of this variant was associated with higher fasting and 30-minute plasma glucose levels, decreased Insulinogenic Index (IGI), and oral disposition index (DIo) (P = 0.009, 0.001, 0.001, and 0.007, respectively) in the normal glucose tolerance (NGT) individuals with normal BMI levels. Furthermore, we also found significant associations between this variant and IGI, corrected insulin response (CIR), and DIo (All P < 0.001) in female individuals whose waist-to-hip ratio (WHR) is greater than 0.85, with considerable heterogeneity (Phet = 0.009, 0.030, and 0.049, respectively) to male participants in the NGT individuals, but not in the impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) individuals. Additionally, no association was observed between this variant and insulin clearance (All P > 0.05).

The MTNR1B rs724030 variant contributes to glycemic traits and islet function, and its effects have sex dimorphisms in the NGT individuals after stratifying by WHR. All these findings provide a basis for accurately assessing islet function in healthy populations and offer a new perspective on precision prevention.

To investigate the association between one-hour post-load plasma glucose (1h-PG) levels and metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic-associated steatohepatitis (MASH).

Clinical data were collected from 538 obese participants who underwent oral glucose tolerance tests (OGTT) and liver biopsy in the Drum Tower Hospital affiliated with the Nanjing University Medical School. Participants were categorized into normal glucose tolerance (NGT), prediabetes (pre-DM), and type 2 diabetes (T2DM) groups, with further stratification of the NGT group into 1h-PG Low and 1h-PG High. The diagnosis of MASLD and MASH was performed using the NASH Clinical Research Network scoring system. Logistic regression analyses were performed to determine the association between each category and MASLD/ MASH.

The prevalence of MASLD and MASH progressively increased across NGT 1h-PG Low, NGT 1h-PG High, pre-DM and T2DM groups. Compared to the NGT 1h-PG Low group, the NGT 1h-PG High group had a significantly higher risk of MASLD (OR 3.27 [95 % CI 1.32;8.09]) and MASH (OR 3.08 [1.55;6.11]), which is similar to the pre-DM group. Additionally, elevated 1h-PG levels were associated with hepatic steatosis, lobular inflammation, and fibrosis. Mediation analysis indicated that Matsuda insulin sensitivity index and disposition index played a sequential mediating role between 1h-PG and hepatic steatosis, accounting for 14.23 % of total effect (β 0.014 [95 % CI 0.002;0.035]).

Elevated 1h-PG levels increase the risk of MASLD and MASH in obese individuals. Early screening and management of MASLD are necessary, even in NGT individuals when 1h-PG levels are ≥8.6 mmol/l.

Night-shift work causes circadian misalignment and impairs glucose metabolism. We hypothesise that food intake during night shifts may contribute to this phenomenon.

This open-label, multi-arm, single-site, parallel-group controlled trial involved a 6 day stay at the University of South Australia's sleep laboratory (Adelaide, SA, Australia). Healthy, non-shift-working adults without obesity (N=55; age 24.5 ± 4.8 years; BMI 24.8 ± 2.8 kg/m2) were assigned to the next available run date and cluster randomised (1:1:1) to fasting-at-night (N=20), snack-at-night (N=17), or meal-at-night (N=18) conditions. One participant withdrew from each group, prior to starting the study. Due to study design, neither participants nor people collecting their measurements could be blinded. Statistical and laboratory staff were concealed to study allocation. Participants were fed at calculated energy balance, with the macronutrient composition of meals being similar across conditions. The primary outcomes were a linear mixed-effects model of glucose, insulin and NEFA AUC in response to a 75 g OGTT that was conducted prior to and after 4 consecutive nights of shift work plus 1 night of recovery sleep. Insulin sensitivity, insulinogenic and disposition indexes were also calculated.

Night-shift work impaired insulin sensitivity, as measured by insulin AUC (p=0.035) and the insulin sensitivity index (p=0.016) across all conditions. Insulin secretion, as measured by the insulinogenic index, was increased in the fasting-at-night condition only (p=0.030), resulting in a day×condition interaction in glucose AUC (p<0.001) such that glucose tolerance was impaired in the meal-at night (+2.00 [95% CI 1.45, 2.56], p<0.001) and snack at-night (+0.96 [0.36, 1.56], p=0.022) conditions vs the fasting-at-night (+0.34 [-0.21, 0.89]) condition. A day×condition interaction was also observed in NEFA AUC (p<0.001), being higher in the meal-at-night (+0.07 [0.03, 0.10]. p=0.001) and snack-at-night (0.01 [-0.03, 0.05], p=0.045) conditions vs the fasting-at-night condition (-0.02 [-0.06, 0.01]). No adverse events occurred.

The timing of food intake has a critical effect on glucose metabolism during simulated night-shift work, which was readily amendable to a meal re-timing intervention.

Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001556437 FUNDING: This work was funded by the National Health and Medical Research Council (NHMRC), APP1099077.

Some individuals with obesity may exhibit fewer metabolic disturbances and face a lower long-term risk of complications; however, the existence of this so-called "metabolically healthy obesity" (MHO) compared to "metabolically unhealthy obesity" (MUO) remains controversial. We hypothesized that children with MHO might have a more favorable profile than children with MUO. Markers of glucose metabolism and insulin sensitivity were compared between children and adolescents diagnosed with MHO and MUO.

This study recruited prospectively 104 children and adolescents (aged 6-16 years, 47 boys) with obesity. All participants underwent an oral glucose tolerance test (OGTT), and a comparative analysis was performed on HOMA-IR, QUICKI, insulin sensitivity index (ISI), insulinogenic index (IGI), disposition index (DI), and oral disposition index (oDI). Glucose metabolism indices were compared in these subgroups according to pubertal status.

Forty-seven children (45.2%) were diagnosed with MHO. The whole-body ISI differed significantly between the MHO and MUO groups (4.02 vs. 2.7, p < 0.01). The IGI was statistically lower in the MHO group compared to MUO (1.26 vs. 1.54, p < 0.01), while neither the DI nor the oDI differed significantly. A higher ISI (4.5 vs. 3.9, p < 0.01) was observed in prepubertal MHO individuals compared to MHO adolescents.

Children classified as MHO according to the more recent criteria exhibit a more favorable metabolic profile than those with MUO. However, a completely healthy profile was not demonstrated in the MHO group, as many crucial metabolic profile parameters were comparable to those observed in the MUO group. The findings of this study indicate that all children with obesity, irrespective of whether they are categorized as having MUO or MHO, necessitate close monitoring.

Sex hormone-binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk. We investigated whether these associations differ by HIV and menopausal status in Black South African women living with (WLWH) and without HIV (WLWOH).

Cross-sectional observational.

Eighty one premenopausal (57 WLWOH, 24 WLWH) and 280 postmenopausal (236 WLWOH, 44 WLWH) women from the Middle-Aged Soweto Cohort (MASC) completed the following measures: circulating SHBG and sex hormones, body composition (dual energy x-ray absorptiometry), oral glucose tolerance test to estimate insulin sensitivity (Matsuda index), secretion (insulinogenic index, IGI) and clearance, and beta-cell function (disposition index, DI). Dysglycaemia was defined as either impaired fasting or postprandial glucose or T2D.

SHBG was higher and total and free testosterone were lower in postmenopausal WLWH than WLWOH (all p≤0.023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance and DI and inversely with HOMA-IR (all p<0.011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (p=0.043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (p=0.021), and positively associated with HOMA-IR in premenopausal and not post-menopausal women (p=0.015 for interaction).

We show for the first time that midlife African WLWH have higher SHBG and lower total and free testosterone than WLWOH, which corresponded to their higher beta-cell function, suggesting a putative protective effect of SHBG on T2D risk in WLWH.

Diabetes mellitus is a prevalent chronic disease that is becoming increasingly common worldwide and can lead to a number of dangerous complications. The Wnt signaling pathway is important for the onset and progression of diabetes. Wnt3a is a typical Wnt ligand that can increase the stability of β-catenin, control TCF7L2 expression, promote β-cell proliferation, and reduce apoptosis.

The involvement of the Wnt3a/β-catenin/TCF7L2 signaling pathway in the development of diabetes and associated problems related to the kidneys is reviewed in this article.

We believe that a thorough comprehension of the molecular connections between diabetes and signaling pathways will eventually lead to improved diabetes management.

The present study investigated the effect of low vs high-dietary-Advanced Glycation End products-based diets on oral disposition index-(DIo)-a marker of islet β-cell function and cardiometabolic risks factors in 38-overweight and obese Asian Indian-adults (aged 25-45 years with body-mass-index (BMI) ≥23kg/m2) through 12-week isocaloric crossover feeding trial. Biochemical-measures included-glucose tolerance test (GTT), Insulin assay (0,30 and 120 min), lipid-profile, serum-adiponectin, serum-AGE and serum-Thiobarbituric acid reactive substances-(TBARS) assessed both at baseline and end of each intervention. Generalised linear models showed that low-dAGE diet significantly improved in oral disposition index [Least Square Mean (SE), +0.3 (0.1); p = 0.03] compared to high-dAGE diet. The low-dAGE diet also showed a significant reduction in 30-minutes plasmapost-glucose-challenge-value:(-8.1[3.8] (mg/dl) vs 3.8 [3.8] (mg/dl); p = 0.01), serum-AGEs-(-3.2 [0.2] (μg/ml) vs -0.8 [0.2] (μg/ml); p = <0.0001) compared to high-dAGE diet. In summary, low-dAGE diets exhibited improvement in the insulin-sensitivity and reduction in the inflammatory levels compared to high-dAGE diets. Hence, study first time in India revealed that low dAGE diets could be a potential strategy to reduce diabetes risk.

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.

Type 1 diabetes (T1D) results from β-cell destruction due to autoimmunity. It has been proposed that β-cell loss is relatively quiescent in the early years after seroconversion to islet antibody positivity (stage 1), with accelerated β-cell loss only developing around 6-18 months prior to clinical diagnosis. This construct implies that immunointervention in this early stage will be of little benefit, since there is little disease activity to modulate. Here, we argue that the apparent lack of progression in early-stage disease may be an artifact of the modality of assessment used. When substantial β-cell function remains, the standard assessment, the oral glucose tolerance test, represents a submaximal stimulus and underestimates the residual function. In contrast, around the time of diagnosis, glucotoxicity exerts a deleterious effect on insulin secretion, giving the impression of disease acceleration. Once glucotoxicity is relieved by insulin therapy, β-cell function partially recovers (the honeymoon effect). However, evidence from recent trials suggests that glucose control has little effect on the underlying disease process. We therefore hypothesize that the autoimmune destruction of β-cells actually progresses at a more or less constant rate through all phases of T1D and that early-stage immunointervention will be both beneficial and desirable.

Progressive deterioration of β-cell function is a characteristic of type 2 diabetes mellitus (T2DM). We aimed to investigate the relative contributions of clinical factors to β-cell function in T2DM.

In a T2DM cohort of 470 adults (disease duration 0 to 41 years), β-cell function was estimated using insulinogenic index (IGI), disposition index (DI), oral disposition index (DIO), and homeostasis model assessment of β-cell function (HOMA-B) derived from a 75 g oral glucose tolerance test (OGTT). The relative contributions of age, sex, disease duration, body mass index, glycosylated hemoglobin (HbA1c) levels (at the time of the OGTT), area under the curve of HbA1c over time (HbA1c AUC), coefficient of variation in HbA1c (HbA1c CV), and antidiabetic agents use were compared by standardized regression coefficients. Longitudinal analyses of these indices were also performed.

IGI, DI, DIO, and HOMA-B declined over time (P<0.001 for all). Notably, HbA1c was the most significant factor affecting IGI, DI, DIO, and HOMA-B in the multivariable regression analysis. Compared with HbA1c ≥9%, DI was 1.9-, 2.5-, 3.7-, and 5.5-fold higher in HbA1c of 8%-<9%, 7%-<8%, 6%-<7%, and <6%, respectively, after adjusting for confounding factors (P<0.001). Conversely, β-cell function was not affected by the type or duration of antidiabetic agents, HbA1c AUC, or HbA1c CV. The trajectories of the IGI, DI, DIO, and HOMA-B mirrored those of HbA1c.

β-Cell function declines over time; however, it is flexible, being largely affected by recent glycemia in T2DM.

Glucagon-like peptide-1(GLP-1) is a hormone often measured in the short-term following Roux-en-Y gastric bypass (RYGB) due to its elevation and association with improvement of glucose metabolism. We examined the durability of this effect in patients with type 2 diabetes mellitus (DM) in the long term after RYGB.

Obese patients with type 2 DM who had received RYGB 10 years ago (n = 10) were enrolled and a meal tolerance test (MTT) was performed. A matched control group with type 2 DM (n = 5) underwent MTT.

Glucose levels during the MTT did not differ between patients with RYGB and the nonsurgical group. Insulin, C-peptide and GLP-1 levels during MTT were significantly higher in patients with RYGB compared with the nonsurgical group (Area under the curve [AUC] of insulin; 57.4 ± 22.9 vs. 27.7 ± 11.1 mIU/L•hr, P = 0.008; AUC of total GLP-1; 189.4 ± 74.72 vs. 52.13 ± 10.23 pM •hr, P = 0.002), and in particular, peak insulin, C-peptide and GLP-1 levels observed 30-45 min after eating were markedly different from those in the nonsurgical group. Bile acids (BAs) and fibroblast growth factor 19 (FGF-19) levels during MTT were higher in patients with RYGB compared with the nonsurgical group. Peak BAs and FGF-19 levels tended to be higher in the RYGB.

An enhanced GLP-1 response was noted 10 years after RYGB, strongly suggesting a durability of this effect. BAs and FGF-19 were increased in the RYGB group, but not as much as the pronounced increase in GLP-1 secretion.

Obesity disrupts glucose metabolism, leading to insulin resistance (IR) and cardiometabolic diseases. Consumption of cow's milk and other dairy products may influence glucose metabolism. Within the complex matrix of cow's milk, various carbohydrates, lipids, and peptides act as bioactive molecules to alter human metabolism. Here, we summarize data from human studies and rodent experiments illustrating how these bioactive molecules regulate insulin and glucose homeostasis, supplemented with in vitro studies of the mechanisms behind their effects. Bioactive carbohydrates, including lactose, galactose, and oligosaccharides, generally reduce hyperglycemia, possibly by preventing gut microbiota dysbiosis. Milk-derived lipids of the milk fat globular membrane improve activation of insulin signaling pathways in animal trials but seem to have little impact on glycemia in human studies. However, other lipids produced by ruminants, including polar lipids, odd-chain, trans-, and branched-chain fatty acids, produce neutral or contradictory effects on glucose metabolism. Bioactive peptides derived from whey and casein may exert their effects both directly through their insulinotropic effects or renin-angiotensin-aldosterone system inhibition and indirectly by the regulation of incretin hormones. Overall, the results bolster many observational studies in humans and suggest that cow's milk intake reduces the risk of, and can perhaps be used in treating, metabolic disorders. However, the mechanisms of action for most bioactive compounds in milk are still largely undiscovered.

We tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic β-cell function, and postglucose glycemia.

Appendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c ≦ 5.5 %.

In two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized β: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized β: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM.

Low skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic β-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.

Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV.

ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure.

ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children.

Diabetes mellitus (DM) is more common among people living with human immunodeficiency virus (PLWH) compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%), and diabetic (6.9%) PLWH. Glycosylated hemoglobin (HbA1c) and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher body mass index, Ethiopian origin, HIV duration, lower integrase inhibitor exposure, and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1c likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation.

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

This review explores the emerging evidence regarding pathogenesis, future trajectories, treatment options, and phenotypes of youth-onset type 2 diabetes (T2D).

Youth-onset T2D is increasing in incidence and prevalence worldwide, disproportionately affecting First Nations communities, socioeconomically disadvantaged youth, and people of colour. Youth-onset T2D differs in pathogenesis to later-onset T2D and progresses more rapidly. It is associated with more complications, and these occur earlier. While there are limited licensed treatment options available, the available medications also appear to have a poorer response in youth with T2D. Multiple interacting factors likely contribute to this rising prevalence, as well as the increased severity of the condition, including structural inequities, increasing obesity and sedentary lifestyles, and intergenerational transmission from in-utero exposure to maternal hyperglycemia and obesity. Youth-onset T2D is also associated with stigma and poorer mental health, and these impact clinical management. There is an urgent need to develop effective interventions to prevent youth-onset T2D and enhance engagement of affected youth. It is also critical to better understand the differing phenotypes of youth-onset T2D, to effectively target treatments, and to address intergenerational transmission in high-risk populations.

Healthy plant-based diets have been associated with lower risk of type 2 diabetes (T2D). Metabolomics can be leveraged to identify potential pathways through which diet influences disease risk.

This study aimed to identify profiles of serum metabolites reflective of plant-based diets of varying quality and examine associations with cardiometabolic risk and T2D.

We included data from 687 participants of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort. An overall plant-based diet index (PDI), healthy PDI (hPDI), and unhealthy PDI (uPDI) were estimated from food frequency questionnaires. Serum metabolites were assayed using ultraperformance liquid chromatography mass spectrometry. Elastic net regression was used to identify sets of metabolites predictive of each diet index, and metabolite profile scores were calculated as the weighted sum of the selected metabolites. Cross-sectional associations between metabolite profile scores and cardiometabolic measures and prospective associations with incident T2D were evaluated with multivariable-adjusted linear and logistic regressions.

Metabolite profiles for PDI, hPDI, and uPDI consisted of n = 51, 55, and 45 metabolites, respectively. Metabolites strongly positively correlated with diet indices included phosphatidylcholine (16:0/18:3) for PDI, phosphatidylethanolamine (20:1/20:4) and pantothenate for hPDI, and lysophosphatidylglycerol (18:2/0:0), proline, and lauric acid for uPDI. Higher metabolite profile scores for PDI and hPDI were associated with lower glycemia and lipids measures, whereas a higher uPDI metabolite score was associated with higher triglycerides and lower low density lipoprotein cholesterol and high density lipoprotein cholesterol. A higher metabolite score for hPDI was additionally associated with lower adiposity measures, higher liver fat attenuation, higher adiponectin, lower odds of overweight (odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.51, 0.81) and obesity (OR: 0.59; 95% CI: 0.48, 0.74), and lower odds of incident T2D (OR: 0.66; 95% CI: 0.45, 0.97).

Metabolite profiles of different plant-based diets were identified. Metabolite profiles of overall and healthy plant-based diets were associated with favorable cardiometabolic risk profiles.

To identify predictors of incident type 2 diabetes using a mixed meal tolerance test (MMTT).

Adult Indigenous Americans without diabetes (n = 501) from a longitudinal cohort underwent at baseline a 4-h MMTT, measures of body composition, an oral glucose tolerance test, an intravenous glucose tolerance test for acute insulin response (AIR), and a hyperinsulinemic-euglycemic clamp for insulin action (M). Plasma glucose responses from the MMTT were quantified by the total and incremental area under the curve (AUC/iAUC).

At follow-up (median time 9.6 [inter-quartile range: 5.6-13.5] years), 169 participants were diagnosed with diabetes. Unadjusted Cox proportional hazards models, glucose AUC180-min (HR: 1.98, 95% CI: 1.67, 2.34, p < 0.0001), AUC240-min (HR: 1.93, 95% CI: 1.62, 2.31, p < 0.0001), and iAUC180-min (HR: 1.43, 95% CI: 1.20, 1.71, p < 0.0001) were associated with an increased risk of diabetes. After adjustment for covariates (age, sex, body fat percentage, M, AIR, Indigenous American heritage) in three subsequent models, AUC180-min (HR: 1.44, 95% CI: 1.10, 1.88, p = 0.007) and AUC240-min (HR: 1.41, 95% CI: 1.09, 1.84, p < 0.01) remained associated with increased risk of diabetes.

Glucose responses to a mixed meal predicted the development of type 2 diabetes. This indicates that a mixed nutritional challenge provides important information on disease risk.

ClinicalTrials.gov identifier : NCT00340132, NCT00339482.

Type 2 diabetes (T2D) is a prevalent chronic illness with many different options for treatment management. Continuous glucose monitors (CGM) offer physiological data that clinicians can access when making treatment decisions. However, the utility of CGM in management of T2D remains an active area of research. In our work, we demonstrate the feasibility of exploiting raw daily CGM data to estimate the physiological parameters of insulin sensitivity and beta-cell function that correlate with estimates derived from laboratory findings. We use a peak extraction algorithm to extract peaks from daily CGM data and implement a model-based approach to infer physiological parameters. We demonstrate that the inferred parameter estimates of insulin sensitivity and beta-cell function correlate to the ground truth measurements as determined by an oral glucose tolerance test (OGTT).

The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance.

In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight.

One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m2, were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA1c (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001).

Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA1c despite the reduction in medication use, and appears to be safe in routine clinical practice.

ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra.

Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss.

In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538).

Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model.

Individuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

To evaluate burden of postpartum diabetes and other cardiometabolic risk factors among women who test positive for gestational diabetes mellitus (GDM) by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, but negative by alternate criteria.

This prospective cross-sectional study was conducted from 2019 to 2022 and is a sub-study of the CHIP-F cohort (Cohort Study of Indian Women with Hyperglycemia in Pregnancy and their Families).

Study participants (n = 826; 183 with normoglycemia and 643 with GDM using IADPSG criteria) were evaluated at a median (IQR) postpartum interval of 31 (21-45) months. Using the United Kingdom National Institute of Health and Care Excellence (UK NICE), Canadian Diabetes Association (CDA), and Diabetes in Pregnancy Study Group India (DIPSI) criteria, 251 (39.0 %), 148 (23.0 %) and 384 (59.7 %) women who tested positive for GDM by IADPSG criteria, would have tested negative. The incidence of postpartum diabetes among such women was 30.4, 34.3, and 48.2 per 1000 women-years, respectively, which was significantly higher than those testing negative by both IADPSG and UK NICE (5.0 per 1000 women-years), IADPSG and CDA (9.2/1000 women-years) and IADPSG and DIPSI criteria (5.0/1000 women-years). The burden of obesity and metabolic syndrome was also significantly higher in such women.

We found a significant burden of postpartum diabetes and cardiometabolic risk factors among women who tested positive for GDM by IADPSG, but negative by alternate criteria. There are potential clinical implications of a "failed" diagnosis for future cardiometabolic diseases that need to be carefully examined.

Pediatric obesity is characterized by insulin resistance, yet it remains unclear whether insulin resistance contributes to abnormalities in glucagon and incretin secretion.

To examine whether fasting and stimulated glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations differ between children and adolescents with obesity and insulin resistance (OIR), obesity and normal insulin sensitivity (OIS), and controls with normal weight (NW).

80 (34 boys) children and adolescents, aged 7-17 years with OIR (n = 22), OIS (n = 22), and NW (n = 36) underwent an oral glucose tolerance test with measurements of serum insulin, plasma glucose, glucagon, total GLP-1, and total GIP. Homeostatic model assessment of insulin resistance (HOMA-IR), single point insulin sensitivity estimator (SPISE), Matsuda index, insulinogenic index (IGI), and oral disposition index (ODI) were calculated.

Fasting concentrations of glucagon and GLP-1 were higher in the OIR group, with no significant differences for GIP. The OIR group had higher glucagon total area under the curve (tAUC0-120) and lower GLP-1 incremental AUC (iAUC0-120), with no significant differences in GIP iAUC0-120. Higher fasting glucagon was associated with higher HOMA-IR, lower Matsuda index, lower SPISE, higher IGI, and higher plasma alanine transaminase, whereas higher fasting GLP-1 was associated with higher HOMA-IR, lower Matsuda index, and lower ODI. Higher glucagon tAUC0-120 was associated lower SPISE and lower Matsuda index, whereas lower GLP-1 iAUC0-120 was associated with a higher HOMA-IR, lower Matsuda index, and lower ODI.

Children and adolescents with OIR have elevated fasting concentrations of glucagon and GLP-1, higher glucagon and lower GLP-1 responses during an OGTT compared to those with OIS and NW. In contrast, individuals with OIS have similar hormone responses to those with NW.

Insulin sensitivity and secretion indices can be useful tools in understanding insulin homeostasis in children at risk for diabetes. There have been few studies examining the reproducibility of these measures in pediatrics.

To determine whether fasting or oral glucose tolerance test (OGTT)-derived insulin measures would be more reproducible and whether there would be differences based on weight, sex, race, and pubertal status.

Observational study.

Clinical research unit.

Two hundred fifty-seven overweight/obese (BMI ≥ 85th%, n = 186) and normal weight (BMI < 85th%, n = 71) children without diabetes between ages of 8 and 17 were included in the study.

OGTT tests performed in study participants at two separate visits within a 3-week period. We performed two formal oral glucose tolerance tests within a 3-week period. The reproducibility of fasting measures was compared with OGTT-derived measures by weight categories and compared by weight, sex, race, and pubertal status. Comparisons were made between the correlation coefficients of fasting vs. OGTT-derived measures and between normal weight vs. obese/overweight participants, male vs. female, White vs. Black, and pre- vs. post-midpubertal. Intraclass correlation coefficients were calculated for each comparison as well.

For insulin sensitivity, the OGTT-derived measure was more reproducible than the fasting measures. There were no significant differences in reproducibility in the overweight/obese population compared to the normal weight population nor by sex, race, or pubertal status.

Nonfasting insulin sensitivity measures are more reproducible than fasting insulin sensitivity measures, regardless of weight category. Insulin secretion measures have poor reproducibility overall. Weight status, sex, race, and midpubertal stage do not impact the reproducibility of insulin sensitivity and secretion measures.

The Asian Indian Beta Cell function (ABCs) in Infants Study examined the associations of maternal weight on infant pancreatic beta cell function across 7 months postpartum. Pregnant women aged 18-35 years were recruited in Hyderabad, India. Women were classified by first trimester weight as underweight (UW), BMI < 18.5 kg/m2; normal weight (NW), BMI 18.5-22.9 kg/m2; or overweight (OW), BMI 23.0 through <28.5 kg/m2. At age > 7 months, infants had an oral glucose tolerance test (OGTT, 1.75 g glucose/kg bodyweight) following a 3 h fast. Infant blood samples were assayed for C-peptide and glucose. Infant beta cell function (HOMA2-B; disposition index, DI) and insulin resistance (HOMA2-IR) were compared across maternal weight groups. Mothers (UW n = 63; NW n = 43; OW n = 29) had similar age at delivery and second trimester 50 g glucose challenge test results. Cord HOMA2-B values were 51% greater for IUW (83.5, SD 55.2) and 44% greater for IOW (79.9, SD 60.8) vs. INW (55.4, SD 51.5), forming a U-shaped relationship between maternal weight and HOMA2-B. No qualitative differences in HOMA2-IR were found at birth. However, at 7 months postpartum, HOMA2-IR changed most within IUW (-64% median reduction) and changed the least in IOW (-7% median reduction). At seven months postpartum, DI was higher in IUW vs. the other groups (geometric mean IUW 1.9 SD 2.5; INW 1.3 SD 2.6 or vs. IOW mean 1.2 SD 3.7), reflecting a +49% difference in DI. Evidence from this study illustrates adaptations in the pancreatic functional response of infants associated with the maternal nutritional environment.