Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.
ABSTRACT: The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D.
Project description:Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D), spurring great interest in the possibility of treating patients with this hormone. The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.
Project description:Sodium-glucose transport protein 2 (SGLT2) inhibitors are a class of anti-diabetic agents; however, concerns have been raised about their potential to induce euglycemic ketoacidosis and to increase both glucose production and glucagon secretion. The mechanisms behind these alterations are unknown. Here we show that the SGLT2 inhibitor (SGLT2i) dapagliflozin promotes ketoacidosis in both healthy and type 2 diabetic rats in the setting of insulinopenia through increased plasma catecholamine and corticosterone concentrations secondary to volume depletion. These derangements increase white adipose tissue (WAT) lipolysis and hepatic acetyl-CoA content, rates of hepatic glucose production, and hepatic ketogenesis. Treatment with a loop diuretic, furosemide, under insulinopenic conditions replicates the effect of dapagliflozin and causes ketoacidosis. Furthermore, the effects of SGLT2 inhibition to promote ketoacidosis are independent from hyperglucagonemia. Taken together these data in rats identify the combination of insulinopenia and dehydration as a potential target to prevent euglycemic ketoacidosis associated with SGLT2i.
Project description:BACKGROUND:Enthusiasm for the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as an adjunctive treatment in type 1 diabetes (T1D) has been offset by the possible increased risk of diabetic ketoacidosis (DKA). Since pump-treated T1D patients are susceptible to DKA due to infusion site problems, this study was undertaken to assess how treatment with SGLT2i affects patterns of early metabolic decompensation following suspension of basal insulin. METHODS:Ten T1D participants (age 19-35 years, duration 10?±?8 years, A1c 7.4%?±?0.8%) underwent overnight pump suspension studies before and after treatment with canagliflozin (CANA). On both nights, basal insulin was suspended at 3 AM and plasma glucose (PG), ?-hydroxybutyrate (BHB), free fatty acids (FFA), plasma insulin (PI), and glucagon were measured. Studies were terminated 6?h after suspension or if PG rose to >350?mg/dL or BHB >2.5?mmol/L. RESULTS:PI levels at the start of suspension were reduced by 30% after CANA treatment (44?±?11?uU/mL vs. 31?±?10?uU/mL, P?<?0.01), but baseline PG, BHB, FFA, and glucagon levels were not significantly different. During the suspension, PG rose from 104?±?10 to 301?±?21?mg/dL before treatment, but only from 109?±?8 to 195?±?14?mg/dL after treatment (P?=?0.002 vs. pretreatment values). On the other hand, CANA treatment did not significantly affect the magnitude of increases in FFA, BHB, and glucagon levels during the suspension study. CONCLUSION:These data indicate that SGLT2i do not accelerate the rate of ketogenesis following the interruption of basal insulin infusion in T1D. Rather, the failure of patients to promptly recognize early metabolic decompensation relates to the much more gradual rise in PG levels.
Project description:INTRODUCTION:Diabetic ketoacidosis (DKA) is associated with inflammation and increased lipolysis. The macrophage activation marker, soluble CD163 (sCD163), is associated with obesity, non-alcoholic fatty liver disease and type 2 diabetes. We aimed to investigate whether sCD163 correlates with key elements of lipolysis in type 1 diabetes patients during mild DKA. MATERIALS AND METHODS:We investigated nine patients with type 1 diabetes twice during: (i) euglycemic control conditions and a bolus of saline; and (ii) hyperglycemic ketotic conditions induced by lipopolysaccharide administration combined with insulin deprivation. Blood samples, indirect calorimetry, palmitate tracer and adipose tissue biopsies were used to investigate lipid metabolism. RESULTS:We observed a significant increase in plasma sCD163 levels after lipopolysaccharide exposure (P < 0.001). Concentrations of sCD163 were positively correlated with plasma concentrations of free fatty acids, palmitate rate of appearance and lipid oxidation rates, and negatively correlated to the expression of G0/G1 switch 2 gene messenger ribonucleic acid content in adipose tissue (P < 0.01 for all). Furthermore, sCD163 levels correlated positively with plasma peak concentrations of cortisol, glucagon, tumor necrosis factor-?, interleukin-6 and interleukin-10 (P < 0.01 for all). Data on lipolysis and inflammation have previously been published. CONCLUSIONS:Macrophage activation assessed by sCD163 might play an important role in DKA, as it correlates strongly with important components of lipid metabolism including free fatty acids, palmitate, lipid oxidation, G0/G1 switch 2 gene and pro-inflammatory cytokines during initial steps of DKA. These results are novel and add important knowledge to the field of DKA.
Project description:AIMS:To compare diabetes patients with hyperglycaemic hyperosmolar state (HHS), diabetic ketoacidosis (DKA), and patients without decompensation (ND). METHODS:In total, 500,973 patients with type 1 or type 2 diabetes of all ages registered in the diabetes patient follow-up (DPV) were included. Analysis was stratified by age (??/?>?20 years) and by manifestation/follow-up. Patients were categorized into three groups: HHS or DKA-during follow-up according to the most recent episode-or ND. RESULTS:At onset of diabetes, HHS criteria were met by 345 (68.4% T1D) and DKA by 9824 (97.6% T1D) patients. DKA patients had a lower BMI(-SDS) in both diabetes types compared to ND. HbA1c was higher in HHS/DKA. During follow-up, HHS occurred in 1451 (42.2% T1D) and DKA in 8389 patients (76.7% T1D). In paediatric T1D, HHS/DKA was associated with younger age, depression, and dyslipidemia. Pump usage was less frequent in DKA patients. In adult T1D/T2D subjects, metabolic control was worse in patients with HHS/DKA. HHS and DKA were also associated with excessive alcohol intake, dementia, stroke, chronic kidney disease, and depression. CONCLUSIONS:HHS/DKA occurred mostly in T1D and younger patients. However, both also occurred in T2D, which is of great importance in the treatment of diabetes. Better education programmes are necessary to prevent decompensation and comorbidities.
Project description:Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are common serious acute complications of type 1 diabetes (T1D). The aim of this study was to determine the frequency of SH and DKA and identify factors related to their occurrence in the T1D Exchange pediatric and young adult cohort.The analysis included 13?487 participants in the T1D Exchange clinic registry aged 2 to <26?yr with T1D ?2?yr. Separate logistic regression models were used to evaluate the association of baseline demographic and clinical factors with the occurrence of SH or DKA in the prior 12?months.Non-White race, no private health insurance, and lower household income were associated with higher frequencies of both SH and DKA (p?<?0.001). SH frequency was highest in children <6?yr old (p?=?0.005), but across the age range, SH was not associated with hemoglobin A1c (HbA1c) levels after controlling for other factors (p?=?0.72). DKA frequency was highest in adolescents (p?<?0.001) and associated with higher HbA1c (p?<?0.001).Our data show that poor glycemic control increases the risk of DKA but does not protect against SH in youth and young adults with type 1 diabetes. The high frequencies of SH and DKA observed in disadvantaged minorities with T1D highlight the need for targeted interventions and new treatment paradigms for patients in these high risk groups.
Project description:Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due to associated weight loss, low risk of hypoglycemia, and improved cardiorenal outcomes seen in persons with type 2 diabetes mellitus. The increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA, has led many to be wary of their use in T1D, especially given limited pediatric data and data regarding cardiorenal protection in this population. The phase 3 trials of these agents in T1D have yielded lower HbA1c, decreased total daily insulin dose, and small but significant weight loss with no increase in hypoglycemia. These trials also reported increased risks of genital mycotic infection and DKA. SGLT inhibitors have been approved as adjunctive therapy to insulin in adults with T1D in Europe and Japan, but the United States Food and Drug Administration has rejected similar applications. Although approaches to mitigate the risk of DKA have been developed, no randomized trials using such tools have been conducted. More research is needed to minimize the risk of DKA and to better evaluate the cardiorenal impact of these agents in persons with T1D.
Project description:INTRODUCTION:Diabetic ketoacidosis (DKA) is a serious complication of diabetes. DKA is associated with poorer cognition in children with type 1 diabetes (T1D), but whether this is the case in older adults with T1D is unknown. Given the increasing life expectancy in T1D, understanding the role of DKA on brain health in older adults is crucial. RESEARCH DESIGN AND METHODS:We examined the association of DKA with cognitive function in 714 older adults with T1D from the Study of Longevity in Diabetes. Participants self-reported lifetime exposure to DKA resulting in hospitalization; DKA was categorized into 0 hospitalization, 1 hospitalization or ?2 hospitalizations (recurrent DKA). Global and domain-specific cognition (language, executive function/psychomotor speed, episodic memory and simple attention) were assessed. The association of DKA with cognitive function was evaluated via linear and logistic regression models. RESULTS:Twenty-eight percent of participants (mean age=67 years; mean age at diagnosis=28 years; average duration of diabetes=39 years) reported a lifetime history of DKA resulting in hospitalization (18.5% single DKA; 9.7% recurrent DKA). In fully adjusted models, those with recurrent DKA had lower global cognitive function (?=-0.13; 95%?CI -0.22 to 0.02) and lower scores on the executive function/psychomotor speed domain (?=-0.34; 95%?CI -0.51 to 0.17). Individuals with recurrent DKA were also more likely to have the lowest level of cognitive function on the executive function/psychomotor speed domain (defined as 1.5 SD below the population mean; OR=3.26, 95%?CI 1.43 to 7.42). CONCLUSIONS:Among 714 older adults with T1D, recurrent DKA was associated with lower global cognitive function, lower scores on the executive function/psychomotor speed domain and 3.3 times greater risk of having the lowest level of cognitive function in our sample on the executive function/psychomotor speed domain. These findings suggest that recurrent DKA may negatively impact the brain health of older patients with T1D and highlight the importance of DKA prevention.
Project description:<h4>Introduction</h4>There is no information on the factors that influence the time required to induce resolution of diabetic ketoacidosis (DKA). New methods are currently available for bedside measurement of serum 3-hydroxybutyrate (3HB). The aim of this study was to determine the relationship between serum 3HB and the time to DKA resolution.<h4>Methods</h4>We reviewed the medical records of patients with type 1 diabetes (T1D) and a history of DKA who were admitted to the Department of Pediatrics, Osaka City University Hospital, between November 2008 and October 2018. DKA resolution was defined as 3HB below 1.0 mmol/L as measured by a bedside ketone meter.<h4>Results</h4>Data of 52 T1D-DKA episodes were analyzed (median age, 8.0 years; 20 male patients; 32 female patients; new T1D diagnosis, n = 13; established diagnosis, n = 39). In all cases, correction of serum 3HB was an important aspect of T1D management. The median time to DKA resolution (defined as the time from the start of insulin infusion until the fall of 3HB level to below 1.0 mmol/L) was 11 and 10 h in new and established T1D cases, respectively. 3HB on admission and the required insulin infusion dose per body weight, but not blood pH level on admission, correlated with time to DKA resolution. There was no relationship between blood pH level and 3HB on admission.<h4>Conclusions</h4>Our results showed that DKA resolution could be achieved within 10-11 h when DKA treatment is guided by bedside 3HB monitoring without any severe complications. Blood 3HB level is a potentially suitable marker for the severity and resolution of DKA.
Project description:<h4>Objectives</h4>To summarise incidence and prevalence of diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D) for the overall patient population and different subgroups (age, sex, geographical region, ethnicity and type of insulin administration).<h4>Design</h4>Systematic literature review (SLR).<h4>Data sources</h4>Medline (via PubMed) and Embase (1 January 2000 to 23 June 2016).<h4>Study selection</h4>Peer-reviewed observational studies with reported data on the incidence or prevalence of DKA in T1D adults were included. A single reviewer completed the study screening and selection process and a second reviewer performed an additional screening of approximately 20% of the publications; two reviewers independently conducted the quality assessment; the results were narratively synthesised.<h4>Results</h4>Out of 1082 articles, 19 met the inclusion and exclusion criteria, with two additional studies identified that did not specify the patient age range and are therefore not included in the SLR. Overall, eight studies reported incidence with a range of 0-56 per 1000 person-years (PYs), with one outlying study reporting an incidence of 263 per 1000 PYs. Eleven studies reported prevalence with a range of 0-128 per 1000 people. Prevalence of DKA decreased with increasing age. Subgroup analyses were performed using data from no more than two studies per subgroup. There was a higher prevalence of DKA reported in women, non-whites and patients treated with insulin injections compared with men, whites and patients using continuous subcutaneous insulin infusion pumps, respectively.<h4>Conclusions</h4>To our knowledge, this is the first SLR on the epidemiology of DKA in T1D adults. Despite an increasing prevalence of T1D in recent years, DKA in adults has been poorly characterised. In an era when the benefit-risk profiles of new antidiabetic therapies are being evaluated, including the potential risk of DKA, there is a clear need to better elucidate the expected rate of DKA among T1D adults.