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Background/aim: To examine if insulin resistance is associated with markers of glycemic, cardiometabolic and atherosclerotic risk in non-obese, non-prediabetic individuals compared to insulin sensitive subjects matched for BMI, gender, and age., Methods: Of 1860 patients from STOP DIABETES study, 624 had normal fasting plasma glucose, body mass index < 30, and HbA1c < 5.7%. All received oral glucose tolerance test (OGTT). Insulin sensitivity was quantitated using Matsuda index: <25th percentile = Insulin Resistant (IR) (n=151) and ≥ 25th percentile = Insulin Sensitive (IS) (n=473). Measures of dysglycemia and cardiometabolic risk were compared between insulin resistant subjects (n=151) and subset of insulin sensitive individuals who were matched for BMI, gender, age (n=151). Carotid intima media thickness (CIMT) and carotid plaque were measured in 65 IR and 76 IS individuals., Results: Compared to matched insulin sensitive patients, insulin resistant non-obese subjects demonstrated increased indicators of glycemic and cardiometabolic risk including: increased 60-minute plasma glucose and percentage of patients with 60-minute plasma glucose > 155mg/dL; increased 120-minute plasma glucose; unrecognized impaired glucose tolerance (IGT) and type 2 diabetes (T2D), decreased disposition index; increased systolic and diastolic blood pressure; elevated plasma triglycerides; reduced HDL cholesterol; increased triglyceride/HDL ratio and hs-CRP. The presence, size, and number of carotid plaques was greater in the insulin resistant group., Conclusion: Approximately 1 in 4 non-obese patients in this population with normal fasting glucose and HbA1c were insulin resistant. In these non-obese subjects, insulin resistance was associated with multiple indicators of dysglycemia and cardiometabolic risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Context: Sustained increases in plasma glucose promote skeletal muscle insulin resistance independent from obesity and dyslipidemia (ie, glucotoxicity). Skeletal muscle lipids are key molecular determinants of insulin action, yet their involvement in the development of glucotoxicity is unclear., Objective: To explore the impact of mild physiologic hyperglycemia on skeletal muscle lipids., Design: Single group pretest-posttest., Participants: Healthy males and females with normal glucose tolerance., Interventions: 72-hour glucose infusion raising plasma glucose by ~50 mg/dL., Main Outcome Measures: Skeletal muscle lipids, insulin sensitivity, lipid oxidation., Results: Despite impairing insulin-mediated glucose disposal and suppressing fasting lipid oxidation, hyperglycemia did not alter either the content or composition of skeletal muscle triglycerides, diacylglycerides, or phospholipids. Skeletal muscle ceramides decreased after glucose infusion, likely in response to a reduction in free fatty acid concentrations., Conclusions: Our results demonstrate that the major lipid pools in skeletal muscle are unperturbed by sustained increases in glucose availability and suggest that glucotoxicity and lipotoxicity drive insulin resistance through distinct mechanistic pathways., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The results of the present study demonstrate that beta cell function in newly diagnosed T2DM patients is the key predictor of response to glucose lowering medications and provides a practical tool (C-Pep120 /C-Pep0) to guide the choice of glucose lowering agent., Objective: This work aims to identify predictors for individualization of antidiabetic therapy in patients with new-onset type 2 diabetes mellitus (T2DM)., Methods: A total of 261 drug-naive participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, with new-onset diabetes, were randomly assigned in a single-center study to receive 1) metformin followed by glipizide and then insulin glargine on failure to achieve glycated hemoglobin A1c (HbA1c) less than 6.5%, or 2) initial triple therapy with metformin/pioglitazone/exenatide. Each patient received a 75-g oral glucose tolerance test (OGTT) prior to start of therapy. Factors that predicted response to therapy were identified using the area under the receiver operating characteristic curve method., Results: Thirty-nine patients started and maintained the treatment goal (HbA1c < 6.5%) on metformin only, and did not require intensification of antihyperglycemic therapy; 54 patients required addition of glipizide to metformin; and 47 patients required insulin addition to metformin plus glipizide for glucose control. The plasma C-peptide concentration (C-Pep)120/C-Pep0 ratio during the OGTT was the strongest predictor of response to therapy. Patients with a ratio less than 1.78 were more likely to require insulin for glucose control, whereas patients with a ratio greater than 2.65 were more likely to achieve glucose control with metformin monotherapy. In patients started on initial triple therapy, the HbA1c decreased independently of the C-Pep120/C-Pep0 ratio., Conclusion: The increase in C-Pep above fasting following glucose load predicts the response to antihyperglycemic therapy in patients with new-onset diabetes. C-Pep120/C-Pep0 provides a useful tool for the individualization of antihyperglycemic therapy in patients with new-onset T2DM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: To examine the effect of combination therapy with canagliflozin plus liraglutide versus each agent alone on beta cell function in type 2 diabetes mellitus (T2DM) patients., Research Design and Methods: A total of 45 poorly controlled (HbA1c = 7%-11%) T2DM patients received an oral glucose tolerance test (OGTT) before and after 16 weeks of treatment with: (i) liraglutide (LIRA); (ii) canagliflozin (CANA); (iii) liraglutide plus canagliflozin (CANA/LIRA)., Results: Both liraglutide and canagliflozin significantly lowered HbA1c with no significant additive effect of the combination on HbA1c (0.89%, 1.43%, and 1.67% respectively). Insulin secretion during the OGTT, measured with (∆C-Pep/∆G)0-120, increased in the 3 groups (from 0.30 ± 0.06 to 0.48 ± 0.10; 0.29 ± 0.05 to 0.98 ± 0.23; and 0.24 ± 0.06 to 1.09 ± 0.12 in subjects receiving CANA, LIRA and CANA/LIRA respectively; P = 0.02 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA), and the increase in insulin secretion was associated with an increase in beta cell glucose sensitivity (29 ± 5 to 55 ± 11; 33 ± 6 to 101 ± 16; and 28 ± 6 to 112 ± 12, respectively; P = 0.01 for CANA vs LIRA, P < 0.0001, CANA/LIRA vs CANA). No significant difference in the increase in insulin secretion or beta cell glucose sensitivity was observed between subjects in LIRA or CANA/LIRA groups. The decrease in HbA1c strongly and inversely correlated with the increase in beta cell glucose sensitivity (r = 0.71, P < 0.001). In multivariate regression model, improved beta cell glucose sensitivity was the strongest predictor of HbA1c decrease with each therapy., Conclusion: Improved beta cell glucose sensitivity with canagliflozin monotherapy and liraglutide monotherapy or in combination is major factor responsible for the HbA1c decrease. Canagliflozin failed to produce an additive effect to improve beta cell glucose sensitivity above that observed with liraglutide., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Many health care providers screen high-risk individuals exclusively with an HbA1c despite its insensitivity for detecting dysglycemia. The 2 cases presented describe the inherent caveats of interpreting HbA1c without performing an oral glucose tolerance test (OGTT). The first case reflects the risk of overdiagnosing type 2 diabetes (T2D) in an older African American male in whom HbA1c levels, although variable, were primarily in the mid-prediabetes range (5.7-6.4% [39-46 mmol/mol]) for many years although the initial OGTT demonstrated borderline impaired fasting glucose with a fasting plasma glucose of 102 mg/dL [5.7 mmol/L]) without evidence for impaired glucose tolerance (2-hour glucose ≥140-199 mg/dl ([7.8-11.1 mmol/L]). Because subsequent HbA1c levels were diagnostic of T2D (6.5%-6.6% [48-49 mmol/mol]), a second OGTT performed was normal. The second case illustrates the risk of underdiagnosing T2D in a male with HIV having normal HbA1c levels over many years who underwent an OGTT when mild prediabetes (HbA1c = 5.7% [39 mmol/mol]) developed that was diagnostic of T2D. To avoid inadvertent mistreatment, it is therefore essential to perform an OGTT, despite its limitations, in high-risk individuals, particularly when glucose or fructosamine and HbA1c values are discordant. Innate differences in the relationship between fructosamine or fasting glucose to HbA1c are demonstrated by the glycation gap or hemoglobin glycation index., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Context: Chronic hyperglycemia worsens skeletal muscle insulin resistance and β-cell function. However, the effect of sustained physiologic hyperglycemia on hepatic insulin sensitivity is not clear., Objective: To examine the effect of sustained physiologic hyperglycemia (similar to that observed in patients with type 2 diabetes) on endogenous (primarily reflecting hepatic) glucose production (EGP) in healthy individuals., Design: Volunteers participated in a three-step hyperinsulinemic (10, 20, 40 mU/m2 per minute) euglycemic clamp before and after a 48-hour glucose infusion to increase plasma glucose concentration by ∼40 mg/dL above baseline. EGP was measured with 3-3H-glucose before and after chronic glucose infusion., Participants: Sixteen persons with normal glucose tolerance [eight with and eight without a family history (FH) of diabetes] participated in the study., Main Outcome Measure: EGP., Results: Basal EGP increased following 48 hours of glucose infusion (from a mean ± SEM of 2.04 ± 0.08 to 3.06 ± 0.29 mg/kgffm⋅ min; P < 0.005). The hepatic insulin resistance index (basal EGP × fasting plasma insulin) markedly increased following glucose infusion (20.1 ± 1.8 to 51.7 ± 6.6; P < 0.005) in both FH+ and FH- subjects., Conclusion: Sustained physiologic hyperglycemia for as little as 48 hours increased the rate of basal hepatic glucose production and induced hepatic insulin resistance in health persons with normal glucose tolerance, providing evidence for the role of glucotoxicity in the increase in hepatic glucose production in type 2 diabetes., (Copyright © 2019 Endocrine Society.)

Objective: To quantify glucose-mediated glucose disposal with and without basal insulin replacement and insulin-mediated glucose disposal in subjects with impaired fasting glucose (IFG)., Research Design and Methods: We used the hyperglycemic/pancreatic clamp and stepped euglycemic clamp techniques to quantify glucose disposal and suppression of endogenous glucose production (EGP) in those with normal glucose tolerance (NGT; n = 14) and those with IFG (n = 14)., Results: Total body glucose-mediated glucose uptake, measured with the hyperglycemic/pancreatic clamp, was not significantly affected by the basal plasma insulin levels in subjects with IFG and those with NGT. Compared with subjects with NGT, those with IFG had significantly lower glucose-mediated glucose uptake (by 15%) during the hyperglycemic clamp performed with and without basal insulin replacement. In contrast, insulin-mediated glucose disposal was comparable in both groups. The suppression of EGP by hyperglycemia was similar in both groups. However, the suppression of EGP by insulin was attenuated in those with IFG compared with those with NGT., Conclusions: The results of the present study have demonstrated that (i) glucose-mediated glucose disposal is impaired in those with IFG; (ii) insulin-mediated glucose uptake in IFG is normal; and (iii) insulin action to suppress EGP is impaired.

Objective: To examine whether lowering plasma glucose concentration with the sodium-glucose transporter-2 inhibitor empagliflozin improves β-cell function in patients with type 2 diabetes mellitus (T2DM)., Methods: Patients with T2DM (N = 15) received empagliflozin (25 mg/d) for 2 weeks. β-Cell function was measured with a nine-step hyperglycemic clamp (each step, 40 mg/dL) before and at 48 hours and at 14 days after initiating empagliflozin., Results: Glucosuria was recorded on days 1 and 14 [mean ± standard error of the mean (SEM), 101 ± 10 g and 117 ± 11 g, respectively] after initiating empagliflozin, as were reductions in fasting plasma glucose levels (25 ± 6 mg/dL and 38 ± 8 mg/dL, respectively; both P < 0.05). After initiating empagliflozin and during the stepped hyperglycemic clamp, the incremental area under the plasma C-peptide concentration curve increased by 48% ± 12% at 48 hours and 61% ± 10% at 14 days (both P < 0.01); glucose infusion rate increased by 15% on day 3 and 16% on day 14, compared with baseline (both P < 0.05); and β-cell function, measured with the insulin secretion/insulin resistance index, increased by 73% ± 21% at 48 hours and 112% ± 20% at 14 days (both P < 0.01). β-cell glucose sensitivity during the hyperglycemic clamp was enhanced by 42% at 14 hours and 54% at 14 days after initiating empagliflozin (both P < 0.01)., Conclusion: Lowering the plasma glucose concentration with empagliflozin in patients with T2DM augmented β-cell glucose sensitivity and improved β-cell function.

Objective: To examine the efficacy and safety of combination therapy with exenatide plus pioglitazone vs basal/bolus insulin in patients with poorly controlled type 2 diabetes mellitus (T2DM) with very high hemoglobin A1c (HbA1c) (>10%) receiving sulfonylurea plus metformin and with a long duration of disease., Design and Participants: Participants (n = 101) in the Qatar Study with very poor glycemic control (HbA1c >10%) and a long duration of diabetes (10.9 years) receiving maximum/near-maximum doses of sulfonylurea plus metformin were randomly assigned to receive pioglitazone plus weekly exenatide (combination therapy), or basal plus prandial insulin (insulin therapy), to maintain HbA1c <7.0%., Results: Baseline HbA1c was 11.5% ± 0.2% and 11.2% ± 0.2% (P = not significant) in combination therapy and insulin therapy groups, respectively. At 6 months, combination therapy caused a robust decrease in HbA1c to 6.7% ± 0.1% (∆ = -4.8%) compared with 7.4% ± 0.1% (∆ = -3.8%) in subjects receiving insulin therapy. Combination therapy was effective in lowering the HbA1c independent of sex, ethnicity, or body mass index. Subjects in the insulin therapy group experienced significantly greater weight gain and a 2.5-fold higher rate of hypoglycemia compared with patients receiving combination therapy., Conclusion: Exenatide/pioglitazone combination therapy is an effective and safe therapeutic option in patients with poorly controlled T2DM receiving metformin plus sulfonylurea with very high HbA1c (>10%)., (Copyright © 2017 by the Endocrine Society)

Aim: To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals., Methods: Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3., Results: Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P < .01), whereas the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dL; P < .01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg · min; P < .05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2., Conclusion: Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and β-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves β-cell function without significantly affecting insulin sensitivity.

Background: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals., Research Design and Methods: Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (OGTT) and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT., Results: Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (ΔG0-120) during OGTT by -33 ± 5 mg/dL, -73 ± 9 mg/dL, and -60 ± 12 mg/dL · min, respectively, compared to -13 ± 9, -33 ± 13, and -18 ± 9 reductions in placebo-treated subjects (both P < .01). The incremental area under the plasma C-peptide concentration curve tended to increase in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects. Thus, ΔC-Pep0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 ± 0.005 vs 0.002 ± 0.006; P < .01). Dapagliflozin significantly improved whole-body insulin sensitivity (insulin clamp). Thus, β-cell function, measured as ΔC-Pep0-120/ ΔG0-120 ÷ insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects., Conclusion: Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function.

Aims and Hypothesis: The insulin secretion/insulin resistance (IR) (disposition) index (ΔI/ΔG ÷ IR, where Δ is change from baseline, I is insulin, and G is glucose) is commonly used as a measure of β-cell function. This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by 2 variables: insulin secretion rate (ISR) and metabolic clearance of insulin. We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (ΔCP) (instead of Δ plasma insulin) was plotted against insulin sensitivity., Methods: A total of 441 individuals with impaired glucose tolerance (IGT) from ACT NOW received an oral glucose tolerance test and were randomized to pioglitazone or placebo for 2.4 years., Results: Pioglitazone reduced IGT conversion to diabetes by 72% (P < .0001). ΔI/ΔG vs the Matsuda index of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against the Matsuda index, the curvilinear relationship was completely lost. This discordance was explained by 2 distinct physiologic effects that altered plasma insulin response in opposite directions: 1) increased ISR and 2) augmented metabolic clearance of insulin. The net result was a decline in the plasma insulin response to hyperglycemia during the oral glucose tolerance test. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into the portal circulation to suppress hepatic glucose production while delivering a reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia., Conclusions: These results demonstrate the validity of the disposition index when relating the plasma insulin response to insulin sensitivity but underscore the pitfall of this index when drawing conclusions about β-cell function, because insulin secretion declined despite an increase in the plasma insulin response.

Aim: The aim of this study was to examine the relationship between whole-body insulin-mediated glucose disposal and the fasting plasma glucose concentration in nondiabetic individuals., Research Design and Methods: Two hundred fifty-three nondiabetic subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance received a 75-g oral glucose tolerance test and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-hour plasma glucose concentrations in each group., Results: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2-hour plasma glucose (PG; r = 0.40, P < .0001) but not with the fasting PG. When IFG and NGT individuals were stratified based on their 2-hour PG concentration, the increase in 2-hour PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals., Conclusion: The present results indicate the following: 1) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; 2) the large variability in TGD in IFG and NGT individuals is related to the 2-hour PG concentration; and 3) after adjustment for the 2-hour proglucagon concentration, IFG subjects have comparable TGD with NGT individuals.

Aim: Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the alpha-cell., Methods: Thirty subjects with normal glucose tolerance, 27 with impaired fasting glucose and/or impaired glucose tolerance, and 32 type 2 diabetic subjects were studied with oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Fasting plasma glucagon concentration and plasma glucagon concentration during the OGTT and insulin clamp were measured., Results: During the OGTT, the decrement in the plasma glucagon concentration (area under the curve) was correlated inversely with the fasting plasma glucose concentration (r = -0.35; P < 0.001). As the fasting glucose level increased, the suppression of plasma glucagon progressively diminished. In contrast, during the euglycemic insulin clamp, the suppression of plasma glucagon was not correlated with the fasting plasma glucose concentration and was similar in subjects with normal glucose tolerance, subjects with impaired fasting glucose/impaired glucose tolerance, and diabetic subjects: 18, 23, and 18%, respectively., Conclusion: Insulin-mediated suppression of glucagon secretion is unrelated to the fasting plasma glucose concentration and is not impaired by chronic hyperglycemia. Thus, the defect in plasma glucagon suppression during the OGTT most likely results from impaired glucose-mediated glucagon suppression. The close correlation between fasting plasma glucose concentration and reduced glucagon suppression suggests a glucotoxic effect on alpha-cell function.