Triggering of a Dll4-Notch1 loop impairs wound healing in diabetes.

Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1-4) and ligands (Jagged 1-2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)-Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs.

A protein-rich meal provides beneficial glycemic and hormonal responses as compared to meals enriched in carbohydrate, fat or fiber, in individuals with or without type-2 diabetes.

Introduction: Diet stands as a pivotal modifiable risk factor influencing weight gain and the onset of type-2 diabetes (T2D). This study delves into the variation in glucose and regulatory pancreatic hormone levels subsequent to the consumption of meals with differing macronutrient compositions. Methods: The cohort comprised 20 individuals diagnosed with T2D and 21 without diabetes. Participants underwent a cross-over design, consuming four isocaloric meals (600 kcal) enriched in carbohydrate, fiber, fat and protein. Plasma glucose, insulin and glucagon levels were measured at -30, and -5 min, followed by subsequent measurements every 30 min for 240 min post meal intake. Quantification of alterations in the postprandial state was accomplished through the incremental area under the curve (iAUC) and the incremental peak height for the insulin:glucagon ratio (IGR) and plasma glucose levels. The meal demonstrating the lowest responses across these variables was deemed the optimal meal. Results: Meals rich in protein and fat, and consequently low in carbohydrate, exhibited reduced incremental peak and iAUC for both glucose and the IGR in comparison to the other meals. While the protein-enriched meal neared optimal standards, it proved less efficient for individuals without T2D and possessing a low BMI, as well as in those with T2D and poor glycemic control. Conclusion: Our findings endorse the adoption of protein-enriched, low-carbohydrate meals to curtail the meal-induced anabolic hormonal response while averting excessive fluctuations in glucose levels.

PIONEER REAL Sweden: A Multicentre, Prospective, Real-World Observational Study of Oral Semaglutide Use in Adults with Type 2 Diabetes in Swedish Clinical Practice.

INTRODUCTION: The study was designed to assess outcomes with once-daily oral semaglutide in adults with type 2 diabetes (T2D) naïve to injectable glucose-lowering agents, in Swedish clinical practice. METHODS: In this non-interventional, multicentre study, participants initiated oral semaglutide and were followed for 34-44 weeks. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to end of study (EOS). Secondary endpoints included body weight (BW) change from baseline to EOS, proportion of participants achieving HbA1c < 7%, and proportion achieving both a HbA1c reduction ≥ 1% and BW reduction of ≥ 3% or ≥ 5%, at EOS. Participants completed Diabetes Treatment Satisfaction Questionnaires (DTSQ status/change) and a dosing conditions questionnaire. RESULTS: A total of 187 participants (mean age 62.5 years) initiated oral semaglutide. Baseline mean HbA1c and BW were 7.8% (n = 177) and 96.9 kg (n = 165), respectively. Estimated mean changes in HbA1c and BW were - 0.88%-points (95% confidence interval [CI] - 1.01 to - 0.75; P < 0.0001) and - 4.72% (95% CI - 5.58 to - 3.86; P < 0.0001), respectively. At EOS, 64.6% of participants had HbA1c < 7%, and 22.9% achieved HbA1c reduction of ≥ 1% and BW reduction of ≥ 5%. DTSQ status and change scores improved by 1.44 (P = 0.0260) and 12.3 points (P < 0.0001), respectively. Oral semaglutide was easy or very easy to consume for 86.4% of participants. Most common adverse events (AEs) were gastrointestinal disorders; nine participants (4.8%) had serious AEs; one (0.5%) experienced severe hypoglycaemia. CONCLUSION: In this real-world study population, we observed significant reductions in HbA1c and BW in people living with T2D when prescribed semaglutide tablets as part of routine clinical practice in Sweden, with improved treatment satisfaction among participants and no new safety concerns. TRIAL REGISTRATION: NCT04601753.

Effects of intermittent fasting on periodontal inflammation and subgingival microbiota.

BACKGROUND: Studies on the impact of intermittent fasting on periodontal health are still scarce. Thus, this study evaluated the effects of long-term intermittent fasting on periodontal health and the subgingival microbiota. METHODS: This pilot study was part of a nonrandomized controlled trial. Overweight/obese participants (n = 14) entered an intermittent fasting program, specifically the 5:2 diet, in which they restricted caloric intake to about a quarter of the normal total daily caloric expenditure for two nonconsecutive days/week. Subjects underwent a thorough clinical and laboratory examination, including an assessment of their periodontal condition, at baseline and 6 months after starting the diet. Additionally, subgingival microbiota was assessed by 16S rRNA gene sequencing. RESULTS: After 6 months of intermittent fasting, weight, body mass index, C-reactive protein, hemoglobin A1c (HbA1c), and the cholesterol profile improved significantly (p < 0.05). Moreover, significant reductions were observed in bleeding on probing (p = 0.01) and the presence of shallow periodontal pockets after fasting (p < 0.001), while no significant change was seen in plaque index (p = 0.14). While we did not observe significant changes in α- or ß-diversity of the subgingival microbiota related to dietary intervention (p > 0.05), significant differences were seen in the abundances of several taxa among individuals exhibiting ≥60% reduction (good responders) in probing pocket depth of 4-5 mm compared to those with <60% reduction (bad responders). CONCLUSION: Intermittent fasting decreased systemic and periodontal inflammation. Although the subgingival microbiota was unaltered by this intervention, apparent taxonomic variability was observed between good and bad responders.

Smart Pen Exposes Missed Basal Insulin Injections and Reveals the Impact on Glycemic Control in Adults With Type 1 Diabetes.

BACKGROUND: Adherence to basal insulin injections and the effects of missed basal insulin injections in adults with type 1 diabetes (T1D) were investigated using data from continuous glucose monitoring (CGM) and smart insulin pen devices in a real-world study. METHODS: This was a post hoc analysis of a prospective, real-world study conducted in Sweden. Adults with T1D who were using CGM received a smart insulin pen device (NovoPen 6) for insulin injections. Missed basal insulin doses (≥40 hours between doses) were evaluated over 14-day periods, and the probability of missing basal insulin doses was estimated. Associations between missed basal insulin doses and glycemic outcomes were also explored. RESULTS: Thirty-two patients with 4410 acceptable CGM days (315 14-day periods) were included. The number of missed basal insulin doses ranged from 0 to 4 over 315 14-day periods. The estimated probability of missing at least one basal insulin dose over any given 14-day period was 22% (95% confidence interval: 10%-40%). Missed basal insulin doses were significantly associated with higher mean glycemic levels, higher glucose management indicator, and lower time in range (70-180 mg/dL [3.9-10.0 mmol/L]). Similar results were observed when adjusted for missed bolus insulin doses; age and sex had no statistically significant effect on any glycemic parameter. CONCLUSIONS: This is the first study, based on accurate real-world injection data, to demonstrate the challenge of adherence to basal insulin injections in patients with T1D, and document that just one missed basal injection per week can result in clinically significant changes in glycemic control.

Real-world use of once-weekly semaglutide in patients with type 2 diabetes: pooled analysis of data from four SURE studies by baseline characteristic subgroups.

INTRODUCTION: This post hoc pooled analysis of four real-world studies (SURE Canada, Denmark/Sweden, Switzerland and UK) aimed to characterize the use of once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: The Semaglutide Real-world Evidence (SURE) studies had a duration of ~30 weeks. Changes in glycated hemoglobin (HbA1c) and body weight (BW) were analyzed for the overall population and the following baseline subgroups: GLP-1RA-naïve/GLP-1RA switchers; body mass index <25/≥25-<30/≥30-<35/≥35 kg/m2; age <65/≥65 years; HbA1c <7%/≥7-≤8%/>8-≤9%/>9%; T2D duration <5/≥5-<10/≥10 years. Data for patients achieving treatment targets were analyzed in the overall population and the baseline HbA1c ≥7% subgroup. RESULTS: Of 1212 patients, 960 were GLP-1RA-naïve and 252 had switched to semaglutide from another GLP-1RA. In the overall population, HbA1c was reduced from baseline to end of study (EOS) by -1.1% point and BW by -4.7 kg; changes were significant for all subgroups. There were significantly larger reductions of HbA1c and BW in GLP-1RA-naïve versus GLP-1RA switchers and larger reductions in HbA1c for patients with higher versus lower baseline HbA1c. At EOS, 52.6% of patients in the overall population achieved HbA1c <7%. No new safety concerns were identified in any of the completed SURE studies. CONCLUSIONS: In this pooled analysis, patients with T2D initiating OW semaglutide showed significant improvements from baseline to EOS in HbA1c and BW across various baseline subgroups, including patients previously treated with a GLP-1RA other than semaglutide, supporting OW semaglutide use in clinical practice. TRAIL REGISTRATION NUMBERS: NCT03457012; NCT03631186; NCT03648281; NCT03876015.

The impact of macronutrient composition on metabolic regulation: An Islet-Centric view.

AIM: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR). METHODS: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2 , and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2 , and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at -30, -5, and 0 min, and every 30 min until 240 min after meal ingestion. RESULTS: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels. CONCLUSION: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.

Corrigendum to "Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy".

[This corrects the article DOI: 10.1155/2019/2936962.].

Predictors of normalized HbA1c after gastric bypass surgery in subjects with abnormal glucose levels, a 2-year follow-up study.

Clinical biomarkers can predict normalization of HbA1c after Roux-en-Y gastric bypass (RYGB) surgery, but it is unclear which are the most predictive.The aim of this study was to compare biomarkers for insulin sensitivity and other clinical parameters in the prediction of normalization of HbA1c after RYGB surgery. This study included 99 (23 men) obese subjects (BMI > 35 kg/m2) undergoing a laparoscopic RYGB. Clinical and biochemical examinations were performed pre-operatively and up to 2 years after surgery. Pre-operatively, normal fasting glucose levels were found in 25 individuals (NG), prediabetes in 46 and type 2 diabetes (T2DM) in 28. At baseline IGF-I (SD), IGFBP-1 and adiponectin levels were low while leptin was high. Weight loss was observed in all three groups, most in the prediabetes group. After 2 years HbA1c was decreased in prediabetes and T2DM. In all three groups insulin, HOMA-IR, lipids and blood pressure improved, IGFBP-1 and adiponectin increased and leptin decreased. IGF-I (SD) increased only in T2DM. In those with prediabetes or T2DM (n = 74), HbA1c at 2 years correlated to baseline BMI (r = -0.27, p = 0.028), age (r = 0.43, p < 0.001), HbA1c (r = 0.37, p = 0.001) and IGFBP-1 (r = 0.25, p = 0.038), and was normalized in 45/74 (61%) at 1 year and in 36 subjects (49%) at 2 years. These responders were younger, had higher BMI, larger waist circumference, lower HbA1c and lower IGFBP-1 levels at baseline. In a multiple regression model age (negative, p = 0.021) and waist circumference (positive, p = 0.047) were the only predictors for normalized HbA1c. RYGB normalized HbA1c in 49% at two years follow-up, which was predicted by low baseline IGFBP-1 level, a marker of hepatic insulin sensitivty and insulin secretion. However,. younger age and larger waist circumference were the only predictors of normalized HbA1c in multivariate analysis.

Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy.

OBJECTIVE: Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. RESEARCH DESIGN AND METHOD: 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. RESULTS: We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. CONCLUSION: The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.

Improved glycemic control due to sitagliptin is not related to cortisol or the surrogate marker IGFBP-1 for hepatic insulin sensitivity.

IMPORTANCE: Elevated cortisol levels and dysregulated insulin-like growth factor binding protein-1 (IGFBP-1; a marker of hepatic insulin sensitivity) are both related to insulin resistance and glucose abnormalities. It is unknown whether improvement in these parameters is related to improved glucose metabolism during treatment with sitagliptin. OBJECTIVE: To determine whether improved insulin sensitivity and beta-cell function during treatment with sitagliptin is related to lower cortisol levels and/or improved regulation of IGFBP-1 in patients with recent acute coronary syndrome (ACS) and newly discovered glucose abnormalities. DESIGN: Samples were taken from The BEta-cell function in Glucose abnormalities and Acute Myocardial Infarction (BEGAMI) trial, a double-blinded, placebo-controlled randomized clinical trial on the efficacy and safety of sitagliptin for patients with ACS and newly discovered glucose abnormalities. SETTING: Cardiology departments (cardiac ICU and outpatient clinic) in two hospitals in Stockholm, Sweden. PARTICIPANTS: Subjects hospitalized (or recently hospitalized) for ACS, in whom an oral glucose tolerance test revealed previously unknown glucose abnormalities. INTERVENTIONS: Subjects were randomized to sitagliptin 100mg once daily (n=34) or placebo (n=37) for twelve weeks. Oral glucose tolerance test (OGTT) and randomization occurred after stabilization median 7 days after ACS. MAIN OUTCOMES AND MEASURES: Fasting serum cortisol and IGFBP-1 were analyzed before OGTT, around 8a.m., and after at 10a.m. The latter time point was chosen as the spread in cortisol levels around is small then, allowing improved chances to detect differences between groups. RESULTS: Glucose tolerance and insulin sensitivity improved in both groups, while HbA1c and indices of ß-cell function improved only in the sitagliptin group as reported previously. Both groups displayed decreased cortisol levels around 10a.m. (from 338±21 to 278±14 nmol/L, p=0.038, in the sitagliptin group; from 343±17 to 302±15 nmol/L, p=0.017, in the placebo group), and improved correlation between fasting log-IGFBP-1 and insulin. CONCLUSIONS AND RELEVANCE: These findings suggest that a stress-related elevation in cortisol may have negative impact on glucose tolerance in patients with recent ACS. However, improved glycemic control with sitagliptin does not appear to be related to changes in cortisol levels or hepatic insulin sensitivity as assessed by IGFBP-1.

Sex differences in type 2 diabetes: focus on disease course and outcomes.

BACKGROUND: Women with type 2 diabetes (T2D) are less likely to reach the goals for hemoglobin A1c compared with men, and have higher all-cause mortality. The risk of cardiovascular disease is elevated among both men and women with T2D, however, the risk has declined among men over recent years while it remains stationary in women. Reasons for these sex differences remain unclear, and guidelines for diabetes treatment do not differentiate between sexes. Possible causes for varying outcome include differences in physiology, treatment response, and psychological factors. This review briefly outlines sex differences in hormonal pathophysiology, and thereafter summarizes the literature to date on sex differences in disease course and outcome. METHODS: Systematic searches were performed on PubMed using "sex", "gender", and various glucose-lowering therapies as keywords. Earlier reviews are summarized and results from individual studies are reported. Reference lists from studies were used to augment the search. RESULTS: There is an increased risk of missing the diagnosis of T2D when screening women with only fasting plasma glucose instead of with an oral glucose tolerance test. The impact of various risk factors for complications may differ by sex. Efficacy and side effects of some glucose-lowering drugs differ between men and women. Men with T2D appear to suffer more microvascular complications, while women have higher morbidity and mortality in cardiovascular disease and also fare worse psychologically. CONCLUSION: Few studies to date have focused on sex differences in T2D. Several questions demand further study, such as whether risk factors and treatment guidelines should be sex-specific. There is a need for clinical trials designed specifically to evaluate sex differences in efficacy and outcome of the available treatments.

Gender differences in non-glycemic responses to improved insulin sensitivity by pioglitazone treatment in patients with type 2 diabetes.

Excess cortisol and GH induce insulin resistance, a central feature of type 2 diabetes (T2D). To study whether the insulin sensitizer pioglitazone affects basal cortisol levels and the GH-IGF-I axis in patients with T2D. Forty-eight patients with T2D (men/women = 28:20, age 61 ± 1 years, BMI 31 ± 0.6 kg/m(2)) were treated for 26 weeks with pioglitazone 30-45 mg daily in addition to their preexisting therapy. Insulin, proinsulin, HbA(1c), IGF-I, IGFBP-1, and basal cortisol were analyzed before and after treatment. Pioglitazone decreased proinsulin/insulin ratio and HbA(1c) decreased (HbA(1c) from 7.8 ± 0.2 to 6.6 ± 0.2% in men and from 7.6 ± 0.2 to 6.1 ± 0.2% in women, p < 0.001 in both). There was a redistribution of fat but no change in waist circumference. IGF-I and adiponectin increased (p ≤ 0.001) in both genders. IGFBP-1 increased but significantly only for the whole group (p = 0.033). Triglycerides decreased significantly in women only (p = 0.015). Before treatment, women had lower basal cortisol (p = 0.045). Basal cortisol increased in women (from 390 ± 26 to 484 ± 32 nmol/L, p = 0.020) but not in men and did not differ between genders at week 26. ΔIGFBP-1 correlated with Δcortisol (r = 0.458; p = 0.049) and Δadiponectin (r = 0.600; p = 0.005) in women only. In addition to the known effect of improving insulin sensitivity, pioglitazone increased IGF-I regardless of gender and in women also increased basal cortisol. Increased IGF-I may contribute to improved insulin sensitivity after treatment. There seems to be gender differences in treatment responses to pioglitazone on lipid metabolism and basal cortisol, perhaps correcting different mechanisms of insulin resistance between genders.

Plasma glutaredoxin activity in healthy subjects and patients with abnormal glucose levels or overt type 2 diabetes.

Oxidative stress induced by hyperglycemia is a key factor in the pathogenesis of diabetes complications. Glutaredoxin 1(Grx1) is a cytosolic redox protein that catalyzes GSH-dependent thiol redox reactions and reversible protein S-glutathionylation. In humans, Grx1 antigen has previously been detected in plasma; however, it has hitherto been unclear if plasma Grx1 is enzymatically active, which would indicate an extracellular function of the protein. Given that glucose overload damages cells through oxidative stress responses, we investigated whether postprandial hyperglycemia induces changes in extracellular Grx1 in patients with abnormal glucose tolerance and healthy subjects. Using a novel sensitive fluorescent substrate assay, we demonstrated that plasma Grx consists of active protein. Grx antigen, activity and total antioxidant capacity were significantly elevated in patients compared to healthy subjects. In response to oral glucose tolerance test, Grx activity and antioxidant capacity increased significantly in healthy volunteers, however, not to the high levels of the patients. In conclusion, these results indicate an extracellular function of plasma Grx in blood glucose metabolism. Thus, Grx may be a marker of increased oxidative stress during hyperglycemia in healthy subjects and may be a risk marker of progression toward diabetes onset.

Analyte flux at a biomaterial-tissue interface over time: implications for sensors for type 1 and 2 diabetes mellitus.

OBJECTIVE: The very presence of an implanted sensor (a foreign body) causes changes in the adjacent tissue that may alter the analytes being sensed. The objective of this study was to investigate changes in glucose availability and local tissue metabolism at the sensor-tissue interface in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). METHOD: Microdialysis was used to model implanted sensors. Capillary glucose and subcutaneous (sc) microdialysate analytes were monitored in five T1DM and five T2DM patients. Analytes included glucose, glycolysis metabolites (lactate, pyruvate), a lipolysis metabolite (glycerol), and a protein degradation byproduct (urea). On eight consecutive days, four measurements were taken during a period of steady state blood glucose. RESULTS: Microdialysate glucose and microdialysate-to-blood-glucose ratio increased over the first several days in all patients. Although glucose recovery eventually stabilized, the lactate levels continued to rise. These trends were explained by local inflammatory and microvascular changes observed in histological analysis of biopsy samples. Urea concentrations mirrored glucose trends. Urea is neither produced nor consumed in sc tissue, and so the initially increasing urea trend is explained by increased local capillary presence during the inflammatory process. Pyruvate in T2DM microdialysate was significantly higher than in T1DM, an observation that is possibly explained by mitochondrial dysfunction in T2DM. Glycerol in T2DM microdialysate (but not in T1DM) was higher than in healthy volunteers, which is likely explained by sc insulin resistance (insulin is a potent antilipolytic hormone). Urea was also higher in microdialysate of patients with diabetes mellitus compared to healthy volunteers. Urea is a byproduct of protein degradation, which is known to be inhibited by insulin. Therefore, insulin deficiency or resistance may explain the higher urea levels. To our knowledge, this is the first histological evaluation of a human tissue biopsy containing an implanted glucose monitoring device. CONCLUSIONS: Monitoring metabolic changes at a material-tissue interface combined with biopsy histology helped to formulate an understanding of physiological changes adjacent to implanted glucose sensors. Microdialysate glucose trends were similar over 1-week in T1DM and T2DM; however, differences in other analytes indicated wound healing and metabolic activities in the two patient groups differ. We propose explanations for the specific observed differences based on differential insulin insufficiency/resistance and mitochondrial dysfunction in T1DM versus T2DM.