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Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims/hypothesis: The aim of this study was to assess metabolic flexibility (MetFlex) in participants with type 2 diabetes within the physiologically relevant conditions of sleeping, the post-absorptive (fasting) state and during meals using 24 h whole-room indirect calorimetry (WRIC) and to determine the impact of aerobic training on these novel features of MetFlex., Methods: Normal-weight, active healthy individuals (active; n = 9), obese individuals without type 2 diabetes (ND; n = 9) and obese individuals with type 2 diabetes (n = 23) completed baseline metabolic assessments. The type 2 diabetes group underwent a 10 week supervised aerobic training intervention and repeated the metabolic assessments. MetFlex was assessed by indirect calorimetry in response to insulin infusion and during a 24 h period in a whole-room indirect calorimeter. Indices of MetFlex evaluated by WRIC included mean RQ and RQ kinetic responses after ingesting a standard high-carbohydrate breakfast (RQ BF ) and sleep RQ (RQ sleep ). Muscle mitochondrial energetics were assessed in the vastus lateralis muscle in vivo and ex vivo using 31 P-magnetic resonance spectroscopy and high-resolution respirometry, respectively., Results: The three groups had significantly different RQ sleep values (active 0.823 ± 0.04, ND 0.860 ± 0.01, type 2 diabetes 0.842 ± 0.03; p < 0.05). The active group had significantly faster RQ BF and more stable RQ sleep responses than the ND and type 2 diabetes groups, as demonstrated by steeper and flatter slopes, respectively. Following the training intervention, the type 2 diabetes group displayed significantly increased RQ BF slope. Several indices of RQ kinetics had significant associations with in vivo and ex vivo muscle mitochondrial capacities., Conclusions/interpretation: Twenty-four hour WRIC revealed that physiological RQ responses exemplify differences in MetFlex across a spectrum of metabolic health and correlated with skeletal muscle mitochondrial energetics. Defects in certain features of MetFlex were improved with aerobic training, emphasising the need to assess multiple aspects of MetFlex and disentangle insulin resistance from MetFlex in type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT01911104., Funding: This study was funded by the ADA (grant no. 7-13-JF-53)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims/hypothesis: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality., Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population., Results: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA 1c , BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group., Conclusions/interpretation: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect., Trial Registration: ClinicalTrials.gov NCT01959529.

Aims/hypothesis: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes., Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA 1c ., Results: Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA 1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA 1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49)., Conclusions/interpretation: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality., Trial Registration: ClinicalTrials.gov NCT01959529.

Aims/hypothesis: Whole body insulin resistance results largely from impaired insulin-stimulated glucose disposal into skeletal muscle. We carried out muscle gene expression profiling to identify differentially expressed genes associated with insulin resistance., Methods: Skeletal muscle total RNA samples from six pairs of non-diabetic insulin-resistant and insulin-sensitive Pima Indians matched for percent body fat were analyzed by DDPCR with 90 primer combinations. The mRNA expression concentrations of selected 13 known genes and four expressed sequences tags were measured by quantitative real-time RT-PCR in 50 non-diabetic Pima subjects., Results: From over 6500 displayed DDPCR cDNA bands, 36 of the most differentially expressed cDNAs were identified, revealing 29 unique sequences: 16 known genes, 10 expressed sequences tags and three unknown transcripts. Multiple regression analyses indicated that whole body insulin-mediated glucose disposal rates of the subjects, independent of age, sex, and percent body fat, were negatively correlated with mRNA concentrations of an EST (DD23; r=-0.38, p=0.007), ATP1A2 (r=-0.27, p=0.05), MAP2K4 (r=-0.34, p=0.02), and PRPSAP1 (r=-0.37, p=0.008). Transcript concentrations of DD23 (r=0.27, p=0.05) and MTND4 (r=-0.29, p=0.05) were correlated with plasma insulin concentration, independent of age, sex, and percent body fat., Conclusion/interpretation: Altered expression concentrations of these genes might be causes or consequences of insulin resistance, and these genes serve as candidate susceptibility genes for insulin resistance.

Aims/hypothesis: We carried out global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. This approach also complemented the ongoing genomic linkage analyses to identify genes linked to insulin resistance and diabetes in Pima Indians., Methods: We compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians using oligonucleotide arrays consisting of about 40,600 transcripts of known genes and expressed sequence tags, and analysed the results with the Wilcoxon rank sum test. We verified the mRNA expression of ten differentially (best-ranked) and ten similarly (worst-ranked) genes using quantitative Real Time PCR., Results: There were 185 differentially expressed transcripts by the rank sum test. The differential expressions of two out of the ten best-ranked genes were confirmed and the similar expressions of all ten worst-ranked genes were reproduced., Conclusion/interpretation: Of the 185 differentially expressed transcripts, 20 per cent were true positives and some could generate new hypotheses about the aetiology or pathophysiology of insulin resistance. Furthermore, differentially expressed genes in chromosomal regions with linkage to diabetes and insulin resistance serve as new diabetes susceptibility genes.

Patients with Type II (non-insulin-dependent) diabetes mellitus manifest abnormalities in insulin action and insulin secretion. It is widely accepted that insulin resistance is an early finding, evident before the onset of hyperglycaemia and predictive of the subsequent development of diabetes. Whether abnormalities in insulin secretion also precede and predict diabetes has been debated. However, recent studies clearly indicate that early insulin secretion plays a critical role in maintaining normal glucose homeostasis. Cross-sectional analyses show that acute insulin secretory responses (AIR) to intravenous glucose are lower in subjects with impaired glucose tolerance and those at high risk for developing diabetes. Prospectively, a low AIR predicts the development of diabetes in several populations. In longitudinal studies, AIR declines dramatically as patients progress from normal to impaired glucose tolerance and ultimately to diabetes. Early insulin secretion is important for the rapid and efficient suppression of endogenous glucose production after a meal. Thus, loss of early insulin secretion initially leads to post-prandial hyperglycaemia which, as the disease progresses, worsens to clinical hyperglycaemia. Strategies that enhance early insulin secretion improve glucose tolerance and represent a novel and more physiologic approach to improving glycaemic control in patients with Type II diabetes mellitus.

Aims/hypothesis: Cross-sectional studies indicate that enlarged subcutaneous abdominal adipocyte size is associated with hyperinsulinaemia, insulin resistance and glucose intolerance. To further explore the pathophysiological significance of these associations, we examined prospectively whether enlarged subcutaneous abdominal adipocyte size predicts Type II (non-insulin-dependent) diabetes mellitus., Methods: Body composition (hydrodensitometry), mean subcutaneous abdominal adipocyte size (fat biopsy), insulin sensitivity (hyperinsulinaemic clamp) and the acute insulin secretory response (25-g i.v. GTT) were assessed in 280 Pima Indians with either normal (NGT), impaired (IGT) or diabetic glucose tolerance (75-g OGTT). Subjects with NGT were then followed prospectively., Results: After adjusting for age, sex and per cent body fat, mean subcutaneous abdominal adipocyte size was 19% and 11% higher in subjects with diabetes and IGT, compared with those with NGT (p < 0.001). Insulin sensitivity was inversely correlated with mean subcutaneous abdominal adipocyte size (r = -0.53, p < 0.0001), even after adjusting for per cent body fat (r = -0.31, p < 0.001). In 108 NGT subjects followed over 9.3 +/- 4.1 years (33 of whom developed diabetes), enlarged mean subcutaneous abdominal adipocyte size but not high per cent body fat, was an independent predictor of diabetes, in addition to a low insulin sensitivity and acute insulin secretory response [relative hazard 10th vs 90th centile (95% CI): 5.8 (1.7-19.6), p < 0.005]. In 28 NGT subjects with a 9% weight gain over 2.7 +/- 1.3 years, changes in insulin sensitivity were inversely and independently related to changes in mean subcutaneous abdominal adipocyte size and per cent body fat., Conclusion/interpretation: Although enlarged mean subcutaneous abdominal adipocyte size is associated with insulin resistance cross-sectionally, prospectively, both abnormalities are independent and additive predictors of Type II diabetes.

Aims/hypothesis: We aimed to quantify changes in insulin action and insulin secretion associated with long-term gain, loss, regain, and maintenance of body weight in subjects with normal (NGT) or impaired (IGT) glucose tolerance., Methods: Insulin action (hyperinsulinaemic clamp) and insulin secretion (intravenous glucose challenge) were measured longitudinally in 209 Pima Indians body weight 94.4 +/- 22.8 kg (means +/- SD) 89 women/120 men, 151 NGT/58 IGT[, who either lost (n = 110) or gained (n = 99) weight (-23% to +29%) over 2.6 +/- 2.0 years. Insulin action and insulin secretion were reassessed on a third occasion in 33 subjects who lost at least 5% body weight over 1.5 +/- 0.8 years and then either regained or maintained weight over the subsequent 1.8 +/- 1.1 years., Results: There was a linear negative relation between changes in body weight and changes in insulin-stimulated glucose disposal in subjects with normal glucose tolerance (r = -0.51, p < 0.0001) and impaired glucose tolerance (r = -0.54, p < 0.0001). In contrast, changes in the acute insulin response were positively related to weight changes in subjects with normal glucose tolerance (r = +0.26, p < 0.005) but negatively in those with impaired glucose tolerance (r = -0.51, p < 0.0001). Improvements in insulin action after an average of 10% weight loss were lost with weight regain but largely preserved with weight maintenance., Conclusion/interpretation: Improvements in insulin action are proportional to the amount of weight loss, similar in magnitude to the impairment in insulin action with weight gain, preserved with long-term weight maintenance and similar between subjects with normal and with impaired glucose tolerance. Weight gain could, however, have more detrimental effects in people with impaired glucose tolerance, in whom insulin secretion decreases rather than increases to compensate for the decreased insulin action.

Pima Indians are insulin resistant and hyperinsulinaemic compared with Caucasians. We investigated whether abdominal fat distribution was different between Pimas and Caucasians and whether differences in the amount of visceral fat explained metabolic differences between the groups. Total body fat (absorptiometry) and abdominal fat distribution at L4-L5 (magnetic resonance imaging) were compared in 20 Pima Indians (10 men/10 women) and 20 age-, sex- and BMI-matched Caucasians. Insulin action was measured as glucose disposal during a two-step hyperinsulinaemic-euglycaemic glucose clamp and insulin secretion was assessed in response to oral and intravenous glucose tolerance tests. By design, percent body fat was similar in Pimas and Caucasians. Abdominal visceral and subcutaneous adipose tissue areas were also similar in the two groups (151+/-16 vs 139+/-15 cm2 and 489+/-61 vs 441+/-7 cm2 respectively). Plasma insulin concentrations were higher in Pimas than Caucasians in the fasting state (27+/-6 vs 11+/-2 mU/ml; p < 0.01) and after a 75-g oral glucose load (area under the curve 19975+/-2626 vs 9293+/-1847 mU x l(-1) x 180 min(-1); p < 0.005). Glucose disposal was lower in Pimas than Caucasians during both steps of the clamp and negatively correlated (after adjustment for percent body fat and sex) with visceral adipose tissue in Caucasians (partial r = -0.51, p = 0.03), but not in Pima Indians (r = -0.03, p = 0.92). Insulin secretion was not related to visceral fat independently of percent body fat in either group. We conclude that a relative increase in visceral fat does not explain insulin resistance and hyperinsulinaemia in Pima Indians.