Bernard Zinman’s research while affiliated with Mount Sinai Hospital, Toronto and other places

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Publications (699)


The coordinated changes in insulin sensitivity and insulin secretion associated with the remission of type 2 diabetes following short‐term insulin therapy
  • Article

March 2025

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3 Reads

Diabetes Obesity and Metabolism

Ravi Retnakaran

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Jiajie Pu

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Alexandra Emery

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[...]

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Bernard Zinman

One-Hour Oral Glucose Tolerance Test for the Postpartum Reclassification of Women With Hyperglycemia in Pregnancy

March 2025

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4 Reads

Diabetes Care

OBJECTIVE The International Diabetes Federation recently endorsed a 1-h oral glucose tolerance test (OGTT) as more convenient than the conventional 2-h OGTT. In practice, women with hyperglycemia in pregnancy are advised to undergo a 2-h OGTT within 6 months after delivery, but this test is often not completed, partly owing to its inconvenience for busy mothers. Recognizing the potential advantage of the 1-h OGTT in this setting, we sought to compare 1-h and 2-h OGTT glucose measurements at 3 months postpartum as predictors of dysglycemia (prediabetes/diabetes) over the first 5 years postpartum. RESEARCH DESIGN AND METHODS A total of 369 women across a range of glucose tolerance in pregnancy (from normoglycemia to gestational diabetes [GDM]) underwent multisample 2-h 75-g OGTTs at 3 months, 1 year, 3 years, and 5 years postpartum. Glucose measurements from the 3-month OGTT were ranked as predictors of dysglycemia (both criteria) by change in concordance index (CCI) of Cox proportional hazard regression models. RESULTS At the 3-month OGTT, 1-h glucose identified all but 10 of 70 women concurrently diagnosed with dysglycemia by 2-h glucose, while diagnosing an additional 96 women. The cumulative incidence of dysglycemia progressively increased over 5 years by tertile of 1-h glucose on the 3-month OGTT (P < 0.0001). On regression analyses, the strongest predictor of dysglycemia was 1-h glucose (change in CCI: 16.1%), followed by 2-h glucose (14.9%). In women with GDM, 1-h glucose again emerged as strongest predictor of dysglycemia (13.0%), followed by 2-h glucose (12.8%). CONCLUSIONS The 1-h OGTT may offer a strategy for increasing rates of postpartum reclassification following hyperglycemia in pregnancy.


Role of the liver in the sustained normalisation of A1c over 2 years following short-term insulin therapy in early type 2 diabetes

November 2024

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3 Reads

Diabetes Obesity and Metabolism

Aims: When administered in early type 2 diabetes (T2DM), the strategy of 'induction' with short-term intensive insulin therapy (IIT) followed by 'maintenance' with metformin thereafter can yield outstanding glycaemic control, with some patients achieving A1c in the normal range of its assay. We thus sought to identify determinants of sustained normalisation of A1c in response to this treatment strategy. Materials and methods: In this study, adults with T2DM of mean duration 1.7 ± 1.4 years received induction IIT (glargine, lispro) for 3 weeks, followed by metformin maintenance either with or without periodic 2-week courses of IIT every 3 months for 2 years. Sustained glycaemic normalisation was defined by A1c <6.0% at 2 years. Results: Of 101 participants, 26 achieved A1c <6.0% at 2 years. At baseline, these individuals had lower A1c and fasting glucose than the other participants, along with better beta-cell function. During maintenance therapy from 3 weeks to 2 years, they had greater reduction of adiposity (body mass index: p = 0.02; waist circumference: p = 0.02), hepatic insulin resistance (HOMA-IR: p = 0.02) and ALT (p = 0.005), coupled with relative stabilisation of beta-cell function and glycaemia. On logistic regression analyses, significant independent predictors of normalisation of A1c at 2 years were baseline A1c (adjusted odds ratio [aOR] = 0.01 [95% CI 0.001-0.16], p = 0.001) and the changes in waist circumference (aOR = 0.77 [0.63-0.94], p = 0.012) and ALT (aOR = 0.90 [0.82-0.98], p = 0.019) during maintenance therapy from 3 weeks to 2 years. Conclusions: While lower baseline A1c and greater reduction in central adiposity predicted A1c <6.0% at 2 years as anticipated, the emergence of greater reduction in ALT as a concomitant determinant highlights the role of the liver in the achievement of sustained glycaemic normalisation.


Figure 2. Mean adjusted levels of the following cardiovascular risk factors in the 3 lactation groups at 1, 3, and 5 years post partum, respectively: A, systolic blood pressure; B, diastolic blood pressure; C, fasting glucose; D, low-density lipoprotein (LDL); E, high-density lipoprotein (HDL); F, triglycerides; G, adiponectin; and H, C-reactive protein (CRP). Mean values are adjusted for age, ethnicity, family history of diabetes, current body mass index, total physical activity in the preceding year, and time since delivery. (P values reflect overall effect of lactation group in multiple linear regression models as per analysis of variance test.)
Figure 3. Trajectories of cardiovascular risk factors in the 3 lactation groups between 1 to 5 years post partum: A, systolic blood pressure; B, diastolic blood pressure; C, fasting glucose; D, low-density lipoprotein (LDL); E, high-density lipoprotein (HDL); F, triglycerides; G, adiponectin; and H, C-reactive protein (CRP), after adjustment for age, ethnicity, family history of diabetes, time-dependent body mass index, months since delivery, time-dependent physical activity, and time effect. (P values reflect overall effect of lactation group in generalized estimating equation models as evaluated by Wald test for nested models.)
Continued
Metabolic syndrome component disorders in the 3 lactation groups at 5 years post partum
Sustained Reduction of Subclinical Inflammation in the Years After Breastfeeding
  • Article
  • Full-text available

November 2024

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19 Reads

The Journal of Clinical Endocrinology and Metabolism

Context Lactation is associated with lower future risk of cardiovascular disease (CVD) in women but the mechanism(s) underlying this relationship remain unclear. Objective We sought to characterize the relationship between duration of exclusive breastfeeding and CV risk factors over the first 5 years post partum. Methods In this prospective cohort study, 328 women underwent serial cardiometabolic characterization (anthropometry, blood pressure [BP], lipids, fasting glucose, adiponectin, C-reactive protein [CRP]) at 1 year, 3 years, and 5 years post partum. Outcomes were CV risk factors in 3 groups defined by duration of exclusive breastfeeding: less than 3 months (n = 107), 3 to 6 months (n = 101), and 6 months or more (n = 120). Results The prevalence of metabolic syndrome did not differ between the groups at 3 years but, by 5 years post partum, was higher in women who had exclusively breastfed for less than 3 months than in those who did so for 3 to 6 and 6 months or more, respectively (14.0% vs 6.9% vs 4.2%; P = .02). However, after adjustment for covariates (including body mass index [BMI]), there were no statistically significant differences between groups in BP, glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, or adiponectin. Indeed, the only CV risk factor difference that persisted after covariate adjustment was that women who had exclusively breastfed for less than 3 months had higher CRP both at 3 years (P = .04) and 5 years (P = .01). Moreover, generalized estimating equation analyses with adjustment for covariates (including time-dependent BMI) showed that CRP remained higher over time in these women, as compared to their peers, from 1 year to 3 years to 5 years post partum (P = .03). Conclusion Sustained reduction of subclinical inflammation may contribute to the cardioprotective effect of lactation in women.

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A Glycemic Threshold Above Which the Improvement of β-Cell Function and Glycemia in Response to Insulin Therapy Is Amplified in Early Type 2 Diabetes: The Reversal of Glucotoxicity

September 2024

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19 Reads

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2 Citations

Diabetes Care

OBJECTIVE Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified. RESEARCH DESIGN AND METHODS IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it. RESULTS The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified. CONCLUSIONS The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity.


The impact of time-restricted eating on beta-cell function in adults with type 2 diabetes: a randomized cross-over trial

August 2024

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21 Reads

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1 Citation

The Journal of Clinical Endocrinology and Metabolism

Objective Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM. Research Design and Methods In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127. Results As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003). Conclusion TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity.


Risk of Total MI Events by Type. Types of MI are not mutually exclusive. BMI indicates body mass index, CI confidence interval, eGFR estimated glomerular filtration rate, HbA1c glycated hemoglobin, MI myocardial infarction, n/a not available, PY patient-years. aNegative binomial model includes age as a linear covariate and treatment, sex, baseline BMI category, baseline HbA1c category, baseline eGFR category and geographical region as fixed effects with log (observation time) as offset. bPoisson regression model includes age as a linear covariate and treatment, sex, baseline BMI category, baseline HbA1c category, baseline eGFR category and geographical region as fixed effects with log (time to event) as offset. cNumber of events too small to conduct analyses
Risk of Total Coronary Events with Death/Death Other than Fatal MI as Terminal Event (Sensitivity Analysis). CI confidence interval, MI myocardial infarction. aJoint frailty model includes treatment as a covariate. bFor MI, the main coronary outcome and the expanded coronary outcome, the terminal event was death other than fatal MI; for coronary revascularization and hospitalization for unstable angina, the terminal event was death. In the empagliflozin group, 269 patients (5.7%) died, with 254 (5.4%) dying from a cause other than fatal MI; in the placebo group, 194 patients (8.3%) died, with 183 (7.8%) dying from a cause other than fatal MI. cMI or coronary revascularization. dMI, coronary revascularization, or hospitalization for unstable angina
Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial

July 2024

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41 Reads

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3 Citations

Cardiovascular Diabetology

Background The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized. Methods This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply–demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type. Results There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620–0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61–1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41–1.10)]. Conclusions In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2. Trail Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.



Logistic regression analyses of pre-diabetes/diabetes at 5-years postpartum: (A) Model adjusted for age, ethnicity, family history of DM, pre-pregnancy BMI, and % weight gain from pre-pregnancy to 5-yrs postpartum. (B) Model further adjusted for duration of breastfeeding in 1st year and average total physical activity at 1-year, 3-years and 5-years
Postpartum weight retention and the early evolution of cardiovascular risk over the first 5 years after pregnancy

March 2024

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22 Reads

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7 Citations

Cardiovascular Diabetology

Background The cumulative effect of postpartum weight retention from each pregnancy in a woman’s life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy. Methods In this prospective observational cohort study, 330 women (mean age 35.7 ± 4.3 years, mean pre-pregnancy body mass index 25.2 ± 4.8 kg/m², 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n = 100), weight gain 0–6% (n = 110), and weight gain ≥ 6% (n = 120). Results At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0–6% to weight gain ≥ 6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p = 0.001), HDL (p = 0.02), LDL (p = 0.01), apolipoprotein-B (p = 0.003), Matsuda index (p < 0.0001), HOMA-IR (p < 0.0001), fasting glucose (p = 0.07), and CRP (p = 0.01). Moreover, on logistic regression analyses, weight gain ≥ 6% emerged as an independent predictor of pre-diabetes/diabetes at 5-years (adjusted OR = 3.40, 95%CI: 1.63–7.09). Conclusion Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women.


Citations (64)


... A total of 148 papers meeting the requirements were preliminarily retrieved, and 16 were finally included through layer by layer screening. The basic characteristics of the included references are shown in table II (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This meta-analysis showed that IF significantly reduced SBP and DBP. ...

Reference:

Intermittent fasting for glycemic control in patients with type 2 diabetes: a meta-analysis of randomized controlled trials
The impact of time-restricted eating on beta-cell function in adults with type 2 diabetes: a randomized cross-over trial
  • Citing Article
  • August 2024

The Journal of Clinical Endocrinology and Metabolism

... For non-diabetic patients with anterior ST-elevation MI and LVEF below 50%, dapagliflozin appears to play a role in preventing LV dysfunction and maintaining cardiac function, as demonstrated in the DACAMI trial (55). Furthermore, in patients with T2DM and CVD, empagliflozin reduced the risk of total MI events by 21%, driven by effects on both type 1 and type 2 MIs, according to insights from the EMPA-REG OUTCOME trial (56). Table 2 presents clinical trials investigating the use of SGLT-2i in MI. ...

Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial

Cardiovascular Diabetology

... 11 Previous studies have explored the association between individual LE8 components and cardiovascular risk factors in women with APOs. 12,13 First, the impact of certain LE8 components, such as sleep health and nicotine exposure, on CVD has yet to be discussed within APO population. Second, whether a favourable CVH profile, as assessed using LE8, could attenuate the excess CVD risk associated with prior APOs is not known. ...

Postpartum weight retention and the early evolution of cardiovascular risk over the first 5 years after pregnancy

Cardiovascular Diabetology

... However, if possible, measuring these parameters every 3-6 months would be desirable. Previous mediation analyses in patients with type 2 diabetes have shown that an increase in serum albumin concentration after SGLT2 therapy contributes to the prevention of cardiovascular and renal events [21][22][23] . Serum albumin, which is produced only in the liver, is considered to be an index of severity and a predictor of the prognosis of liver disease, including NAFLD 24 . ...

How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial
  • Citing Article
  • February 2024

Nephrology Dialysis Transplantation

... Destinations include Winnipeg (Manitoba), Thunder Bay, or Sioux Lookout (Ontario). The median age in the community is 22 years, and previous research based on a cohort of caregivers indicates that approximately 70% of women initiate breastfeeding, and 8% and 30% of mothers use alcohol and unprescribed medications (often indicated as opioids) during pregnancy, respectively (Government of Canada 2020; Monteith et al. 2023). The University of Toronto has partnered with Sandy Lake in research initiatives for over 30 years and this project is an extension of this ongoing research partnership through the Sandy Lake Health and Diabetes Project (SLHDP) (Ho et al. 2006;Kakekagumick et al. 2013). ...

Determinants of Anishinabeck infant and early childhood growth trajectories in Northwestern Ontario, Canada: a cohort study

BMC Pediatrics

... We compared the utility of different BcF indices in differentiating different GMs, and ciR 120 and ciR 30 ranked 1st and 2nd in distinguishing t2D from NGM and iGR, respectively. the ciR indices provide more comprehensive assessment of BcF than other indices, such as i/G and Δi/ΔG [21], and have been widely used to evaluate pancreatic β-cell secretory capacity in the clinical practice and research settings [17,31,32]. in our study, a dramatic decrease in ciR 30 and ciR 120 occurred in the iGR state and a loss in postprandial glycemic control preceded glycemic deterioration in the fasting state with disease progression to iGR and t2D. this is consistent with a prior study, conducted in iraq and sweden, demonstrating that ciR predicted t2D onset independent of BMi and WhpR [33]. ...

Future cardiometabolic implications of insulin hypersecretion in response to oral glucose: a prospective cohort study

EClinicalMedicine

... A post hoc analyses SGTL2i EMPA-REG OUTCOME randomized controlled trial demonstrated similar widespread renal protective benefits across KDIGO risk categories with the greatest benefit observed in the higher risk cohorts. 4 The 2024 KDIGO clinical practice guidelines for patients with CKD and diabetes lists the following as recommended goal-directed medical therapy (GDMT): metformin and SGLT2i, followed by nonsteroidal mineralocorticoid receptor antagonists in those with persistent albuminuria >30 mg/g despite other standard-of-care therapies, and GLP-1RA in those not achieving individualized glycemic targets despite standard-of-care therapies (1B evidence). 5 Populations that fall within the high and very high risk KDIGO categories are associated with the highest burden of disease, have the greatest risk of disease progression, and seem to benefit the greatest with rapid implementation of GDMT. ...

Shifts in KDIGO CKD risk groups with empagliflozin: Kidney-protection from SGLT2 inhibition across the spectrum of risk
  • Citing Article
  • October 2023

Journal of Diabetes and its Complications

... Obesitya crucial component of CKM syndromeis highly prevalent and has been declared a global epidemic [4], with 90% of adults in the US meeting criteria for CKM stage 1 or higher [5]. Fortunately, on the basis of cardiovascular outcome trials (CVOTS), GLP1RA therapies have shown beneficial effects on cardiorenal outcomes and weight loss, and therefore represent an important While tirzepatide results in impressive weight loss, definitive data on effects on MACE are pending in two CVOTS: SURPASS-CVOT (NCT04255433) and SURMOUNT-MMO (NCT05556512) [22]. ...

Comparison of Tirzepatide and Dulaglutide on Major Adverse Cardiovascular Events in Participants with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: SURPASS-CVOT Design and Baseline Characteristics
  • Citing Article
  • September 2023

American Heart Journal

... 38 Clearly, deteriorating beta-cell function seems to be a common pathophysiologic defect that distinctly separates the high-risk prediabetes progressors from the non-progressors in women with NGT postpartum. 41 In our cohort, only the 2-h post-glucose load and not the fasting was associated with postpartum dysglycaemia, which could reflect different metabolic states in different ethnic groups. A higher post-glucose load level could reflect defective early and late-phase insulin secretion coupled with peripheral insulin resistance, distinct from those with fasting hyperglycaemia. ...

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy

Diabetologia

... 21 This has led to an increased interest in insulin therapy for a limited period of time, mainly in order to stabilise glycaemia and attempt to partially reverse the underlying pathophysiological pathways by reversing glucose toxicity. 22 In 1984 Andrews et al presented findings from a study involving 13 obese patients with type 2 diabetes which demonstrated that one month ...

Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes