Severe Insulin Resistance Research Articles

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.

7086 Disrupted Mitochondrial Function in Alström Syndrome- A Monogenic Model of Insulin Resistance and Obesity

Abstract Disclosure: S. Ali: None. S. Heising: None. V. Veeranna: None. A. Vincent: None. G.S. Xavier: None. T. Geberhiwot: None. Alström syndrome (ALMS) is a rare monogenic disease typified by severe insulin resistance (IR) and obesity. IR and obesity are cardinal features of metabolic syndrome. The metabolic effects of insulin at key target tissues leads to metabolic haemostasis by promoting glucose and lipid uptake and metabolism to generate energy in cells. Although insulin is a major regulator of fuel metabolism, its effects on mitochondrial ATP production in severe insulin resistance are unclear. RNASeq data from adipose tissue (AT) from patients with ALMS show downregulation of the expression of genes associated with mitochondrial respiratory chain function, pointing towards possible altered mitochondrial function in ALMS. We therefore undertook a detailed assessment of mitochondrial oxidative phosphorylation capacity (OXPHOS) in skeletal muscle (SM) in ALMS. We performed SM biopsy in 10 ALMS and 10 healthy control volunteers that were age, gender and Body Mass Index matched. The SM was subjected to high resolution respirometry, the gold standard method to quantify mitochondrial function ex vivo, using OROBOROS Oxygraph -2k (O2k) system. Overall OXPHOS was higher in control SM compared to ALMS, with maximal respiration of 62.96±19.2 and 44.24 ± 12.53 pmol/(s*mg), respectively (p<0.05).Reduced oxygen influx was observed in ALMS SM in comparison to controls for fatty acid ß oxidation (6.7±5.96 vs 7.87±2.7 pmol/(s*mg);p<0.05, at complex I (19.4 ± 8.98 vs 29.7 ±5.3 pmol/(s*mg);p<0.05, and at complex II (34.98 ±11.75 vs 53.52± 13.2 pmol/(s*mg) ;p<0.05. Mitochondrial membrane integrity was unaffected during these experiments. Therefore, our analysis unveils a consistent reduction in mitochondrial respiration across all the electron transport pathway. This noteworthy finding suggests impairment in respiratory function and the electron transport chain in mitochondria, a crucial aspect of cellular energy metabolism. Several studies have previously linked IR with mitochondrial dysfunction, where insulin-resistant rodents and humans have shown blunted mitochondrial response to ATP generation. Our results align with this body of evidence emphasizing the significance of investigating the underlying mechanism contributing to this phenomenon. These findings could pave the way to exploring potential mitochondrial-targeted therapies to restore mitochondrial function and therefore, improve insulin sensitivity to tackle IR in ALMS. Presentation: 6/2/2024

6588 Insulin Autoimmune Syndrome Presenting with Severe Insulin Resistance and Recurrent Diabetic Ketoacidosis

Abstract Disclosure: E. Looi: None. R. Rosenberg: None. S. Sugar: None. H. Stone: None. A.W. Michels: None. D. Saxon: None. Background: Insulin autoimmune syndrome (IAS) is a rare cause of severe insulin resistance and is typically associated with intermittent hypoglycemia due to insulin antibodies (IA) with high binding capacity and low insulin affinity. However, consideration should be given for atypical presentation of IAS or co-presentation of IAS with type B insulin resistance syndrome (TBIRS) in the absence of hypoglycemia, as described in this case. Case: A 78-year-old African American female (BMI 21 kg/m2) with poorly controlled type 2 diabetes (A1c 11%) experienced recurrent episodes of diabetic ketoacidosis (DKA) despite adherence to escalating insulin doses (310 units daily, 5 u/kg/day). She was referred to endocrinology and continuous glucose monitoring revealed consistently elevated glucose levels (300-400 mg/dL) without hypoglycemia. She had normal renal function, hepatic function, and lipid panel. During a subsequent hospitalization, she required insulin drip rates of 50-70 u/hr. Insulin resistance workup revealed significantly elevated IA level (8.346, normal ≤ 0.010) measured using a fluid-phase radiobinding assay with high insulin binding capacity (1040 U insulin-binding/L blood) and low insulin binding affinity (1.9x107 M), which supported the diagnosis of IAS. Rheumatologic workup for other autoimmune diseases was negative. Due to recurrent DKA episodes, severe insulin resistance without obvious alternative cause, and lack of hypoglycemic events despite low IA binding affinity, co-morbid TBIRS was considered. As there are no commercially available insulin receptor antibody (IRAb) assays, diagnosis could not be confirmed before her condition worsened, and she was admitted for another episode of DKA within a week of being discharged. Due to clinical deterioration and high suspicion for IAS ± TBIRS, treatment with a combination of immunosuppressive agents was initiated in accordance with an NIH protocol (Klubo-Gwiezdzinska J, et al. 2018). Intravenous immune globulin (0.5g/kg/day) was administered over 2 days which resulted in a brief reprieve and followed by significant relapse. Two doses of rituximab (750 mg/m2) and 2 steroid pulses (dexamethasone 40 mg PO daily for 4 days) were then administered 2 weeks apart. Cyclophosphamide 100 mg daily was also started. Her hyperglycemia and insulin requirements subsequently improved, and she was eventually discharged with good glycemic control on a total daily dose of 40 units of insulin (0.5 u/kg/day), an 87.1% reduction in daily insulin requirement. Conclusion: This case demonstrates that IAS - although classically associated with hypoglycemic episodes - may also present with severe insulin resistance and recurrent DKA without hypoglycemia. Whether characterized by high IA binding capacity and affinity or coexisting with IRAb, a combination of immunosuppressants proved effective in treating both TBIRS and IAS in this instance. Presentation: 6/3/2024

5175 A Rare Case of Type B Insulin Resistance Syndrome

Abstract Disclosure: S. Fatima: None. A. Champion: None. S. Ward: None. Q. Aziz: None. K.E. Izuora: None. Introduction: Severe insulin resistance may be defined as a severely diminished response to insulin’s biological effects and is characterized by substantial hyperinsulinemia and impaired glucose response to endogenous and exogenous insulin. We hereby present a rare case of Type B Insulin Resistance Syndrome (TBIRS). Case:40-years old female with history of systemic lupus erythematosus (SLE), diabetes mellitus was admitted with multiple rheumatologic complaints, including arthralgias, oral ulcers, skin rash, and hair loss secondary to SLE flare. Endocrinology was consulted for diabetes management. Her HbA1c had increased from 7.3% to 11.6% in 3 months despite taking Glargine 45 units daily, Lispro 15 units pre-meals and metformin. She noticed 80 lbs weight loss for past 6 months. Her BMI was 26 and exam showed acanthosis of neck, armpits, groin, hair loss on scalp, multiple genital ulcers, and facial rash. She was noted to have refractory hyperglycemia despite high insulin doses. By 14th day of hospitalization, she was on 287 units of insulin (3.4units/kg) daily. We suspected TBIRS in the setting of SLE. Metformin and pioglitazone were started. Further testing showed insulin level 152mIU/ml (2.6-14.9mIU/ml), C-peptide 1.7 ng/ml (1.1-4.4 ng/ml), islet-cell antibody negative, GAD-65 antibody <5 u/ml, insulin antibody 6.5 uU/ml, IGF-1 14 (79-259 ng/ml), adiponectin 13.3 (2.4-17.9 ug/ml), testosterone 7 (8-60 ng/dl), free testosterone <0.2 (0-4.2 pg/ml), total cholesterol 200 mg/dl (<200 mg/dl), triglycerides 85 mg/dl (<150 mg/dl), LDL 154 mg/dl (<100 mg/dl), HDL 29 mg/dl (>60 mg/dl). She was transferred to National Institute of Health for further care. She was confirmed to have TBIRS by insulin receptor antibody testing, started on regular insulin U500 initially, and then switched to IV insulin drip requiring up to 1700 units of insulin per hour. She received methylprednisolone, cyclophosphamide (2 doses), rituximab (2 doses), hydroxychloroquine and IV immunoglobulin. Her stay was complicated by hemophagocytic lymphohistiocytosis. She was discharged on U-500 Regular insulin, 1000 units with breakfast and 500 units with lunch, Prednisone 60 mg daily and Hydroxychloroquine. Two months later she was found unresponsive at home secondary to hypoglycemic seizures. She required dextrose drip and was discharged on Glargine 16 units and Lispro 6 units with meals. Conclusion: TBIRS is caused by a highly specific polyclonal autoantibody against the cell surface insulin receptor that decreases the cellular insulin response and causes refractory hyperglycemia. About 100 cases have been reported in literature. 60% of the cases are associated with SLE. The goal of therapy is to reverse the hypercatabolic state with high doses of insulin and to eliminate the autoantibodies with immunosuppressive therapy. The most common cause of mortality is hypoglycemia. Presentation: 6/3/2024

7137 The Sugar Saga: A Profound Case Of Diabetic Ketoacidosis Due To Enfortumab Vedotin

Abstract Disclosure: P. Aron: None. B. Connell: None. R. Longo: None. J. Upadhyay: None. This is a case of severe hyperglycemia with the use of Enfortumab Vedotin (EV) in the setting of advanced urothelial cancer. EV is a nectin-4-directed antibody-drug conjugate with a microtubule inhibitor approved for treating advanced/recurrent disease. It is the first of its class that is an antibody-drug conjugate (ADC), targeting nectin, but not the first ADC to cause hyperglycemia. Here we present a case of severe insulin resistance requiring insulin infusion at 50 units/hour in addition to subcutaneous insulin all in the setting of EV use.74 year old male with BMI of 28 and HbA1c of 7.5%, managed only with diet was started on EV for metastatic urothelial cancer. Patient received one cycle (3 doses) of EV (on days 1, 8, 15) and thereafter noticed worsening of hyperglycemia with blood glucose of 533 mg/dL, requiring subcutaneous insulin. Patient’s blood glucose readings remained elevated and he was admitted to the hospital as he was found to be in DKA with a pH of 7.2, bicarbonate 14 mmol/L, anion gap of 16 mmol/L and a glucose of 558 mg/dL. The patient was started on intravenous insulin (IV) infusion using insulin infusion protocol titrated up to 14 units an hour with an additional 30 units of glargine. Patients’ clinical condition continued to worsen and he was in septic shock with pressors and on insulin infusion exceeding 55 units/hour, NPH at 50 units, and regular insulin 30 units with glucose persistently above 400 mg/dL. Patient was started on hydrocortisone 50mg every 6h and his blood glucose readings eventually normalized over a span of 1 week. Patient eventually was able to be discharged to rehabilitation with just a correctional humalog insulin. Our case demonstrates DKA as a consequence of severe insulin resistance seen as a side effect of EV. Hyperglycemia is seen in 8% of patients using this medication, but severe cases are mostly seen with high BMI and uncontrolled diabetes. This case illustrates the fact that one needs to be cautious in ALL patients with diabetes when using this drug and warrants screening for DKA/severe insulin resistance if blood glucose is running >250mg/dL. The exact mechanism for hyperglycemia is unknown but it is likely immunomodulatory and therefore treatment with pulse dose steroids may help with overcoming insulin resistance in this setting like in our patient. More research needs to be done to understand mechanisms and establish treatment guidelines for severe insulin resistance and hyperglycemia caused by this medication. Presentation: 6/1/2024

8475 Automated Insulin Delivery System with Concentrated Regular U500 Insulin in Cushing Syndrome

Abstract Disclosure: F. Erenler: None. J. Aurora: None. Background: Concentrated regular U-500 (U-500R) insulin is commonly used in patients with T2DM, who are highly insulin-resistant, requiring more than 200 units of insulin per day. Utilizing U-500R reduces the number of daily injections, decreases injection volume, and improves cost effectiveness. There has been a case report with U-500R in an automated insulin delivery (AID) system with successful results (1). To our knowledge there is no data on AID system use in Cushing patients with T2DM using U-500R. We present a case of a patient with Cushing Syndrome (CS) with poor BG control using >250 units/day of SC U-500R with improved BG control after switching to Omnipod 5 AID system. Clinical Case: A 57 y.o. male initially presented with hypogonadotropic hypogonadism and subsequently diagnosed with ACTH-dependent CS, which is complicated by obesity, uncontrolled T2DM, lower extremity wounds, and DVTs. He was diagnosed with CS with multiple abnormal 1 mg dexamethasone suppression tests (DST) (max AM cortisol 5.9 mcg/dL; RR <1.8 mcg/dL, dexamethasone level 300), elevated urine free cortisol (UFC) (max UFC/Cr 77.6 mcg/mg/L; RR: 5-64 mcg/24-hr) and elevated salivary cortisol (max cortisol 0.2 mcg/dL; RR: <0.09 mcg/dL). He had suppressed cortisol with 8 mg DST. An MRI sella showed left-sided hypoechoic 0.9 cm mass. Desmopressin (DDAVP) stimulation test and Ga-68 DOTATATE-PET scan were negative. As a result of his abnormal MRI sella and elevated cortisol, he underwent transsphenoidal surgery of the left pituitary. Pathology was non-diagnostic for a pituitary adenoma. Post-op 24-hr UFC and 1 mg DST levels remained high. DDAVP stimulation test and Ga-68 DOTATATE-PET were repeated post-op and were negative. Due to complications of CS, he was initially treated with cabergoline, but switched to osilodrostat due to intolerances. He is currently on 2 mg BID dose and 24-hr UFC has been normal since then (UFC 20 mcg/L, Cr 0.67 mg, UFC/Cr 12 mcg/mg/L). He continued to have uncontrolled hyperglycemia despite normalization of UFC. On his CGM data, he was in target range (70-180 mg/dL) 5% of the time despite using U-500R 95 units SC TID. Given his severe hyperglycemia and insulin resistance, he was switched to an AID system with U-500R and his time in target range improved over 60% after a month of use and his total daily dose of insulin decreased to less than 200 units. Conclusion: U-500R proved to be safe and effective with Omnipod 5 AID. To our knowledge, this is the first reported patient with CS using U-500R with Omnipod 5 AID. In patients without CS, the AID algorithm continuously kept BG well below the set target, especially overnight. Notably, our patient did not have this overnight hypoglycemia trend, which should be expected with his disease. We are hoping to increase the awareness of U-500R with AID systems, especially for patients with incurable CS. Reference:1.Aurora J Jr, Saraswat A. J Endocr Soc. 2023;7(Suppl 1):bvad114.873. Presentation: 6/3/2024

Beyond the retina: Lipemia retinalis as a clue to Berardinelli-Seip congenital lipodystrophy syndrome

In this rare and significant scenario, a 15-year-old female recently diagnosed with type 1 diabetes mellitus presented with moderate lipemia retinalis during routine diabetic retinopathy screening. Further investigations revealed elevated triglyceride and cholesterol levels, prompting the diagnosis of Berardinelli-Seip congenital lipodystrophy syndrome. This congenital disorder, characterized by severe insulin resistance and dyslipidemia due to near-total absence of adipose tissue, emphasizes the critical role of interdisciplinary care involving ophthalmologists, endocrinologists, and geneticists. Early recognition of ocular manifestations such as lipemia retinalis is crucial for timely diagnosis and tailored treatment strategies.

THE EFFECT OF OVERWEIGHT AND OBESITY ON DYSLIPIDEMIA: CROSS-SECTIONAL STUDY IN HEART CENTER

Background. Obesity has turned into a worldwide epidemic with increasing prevalence that is associated with excess mortality and morbidity. Obesity is a risk factor for many diseases including cardiovascular disease, the leading cause of death worldwide. Aim of the study was conducted to evaluate the association of obesity with dyslipidemia and hypertension among patients with low, medium and high risk of developing cardiovascular diseases Materials and methods. Cross-sectional study was conducted at the tertiary hospital in Astana, Kazakhstan. In total 216 participants included in this study. Results. Student’s t test was performed to elicit association between body mass index and lipid panel analysis such as cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein, where all p values found to be <0.0001. Consequently, there is a statistically significant association, and increased body mass indexis linked with higher lipids in the body.Obesity increases risk of atherosclerosis 2.81 times in comparison those who have a normal body mass index. Obesity increases risk of coronary angioplasty with stenting 1.91 times in comparison those who did not undergo stenting procedure. Conclusion. Atherogenic dyslipidemia is extremely common in obesity, both in the presence and in the absence of severe insulin resistance, and is probably the main factor in the increased risk of cardiovascular diseases in these people

Characteristics and pregnancy outcomesofsubtypes of gestational diabetes mellitusbased on HOMA-IR and BMI.

To identify the characteristics and pregnancy outcomes across different subgroups of gestational diabetes mellitus (GDM) categorized by insulin resistance index and body mass index (BMI) in early pregnancy. This retrospective study included 1804 women who underwent a 75g-OGTT during 22-28weeks of gestation, categorized into normal glucose tolerance (NGT) (1487) and GDM (317 [17.57%] of the total cohort). Metabolic parameters were assessed, and equation of homeostatic model assessment (HOMA) were utilized to compute indices of insulin resistance (HOMA-IR), β-cell secretory (HOMA-B), and insulin sensitivity (HOMA-%S) in early and mid-pregnancy. The cut-off value of HOMA-IR (1.61) in early pregnancy was determined via ROC curve analysis. This value, combined with pre-pregnancy BMI, further categorized NGT and GDM into six subgroups respectively, based on HOMA-IR levels (≥ 1.61 or < 1.61) and BMI categories (< 18.5kg/m2, 18.5-25kg/m2, or ≥ 25kg/m2). In comparison to women with NGT, those with GDM were notably older, had higher pre-BMI, fasting plasma glucose (FPG), insulin, and lipid levels in early pregnancy. They also exhibited more pronounced insulin resistance in both early and mid-pregnancy, leading to poorer outcomes. Following an oral glucose load, the peaks of glucose and insulin were out of sync in GDM and its subgroups, accompanied by further increases in HOMA-IR, HOMA-B, and a decrease in HOMA-%S, except for the GDM subgroup with HOMA-IR < 1.61/BMI < 18.5kg/m2. Conversely, glucose and insulin secretion in NGT and its subgroups peaked synchronously at 60min. GDM women with HOMA-IR ≥ 1.61/18.5kg/m2 ≤ BMI < 25kg/m2 had higher rates of neonatal jaundice (34.5% vs 13.9%, p < 0.0001), LGA (28.9% vs 13.2%, p = 0.001), macrosomia (9.8% vs 3.7%, p = 0.025) compared to peers, while in GDM women with HOMA-IR ≥ 1.61/BMI ≥ 25kg/m2, the rates of LGA and macrosomia were 26.6% and 8.4%, respectively. The GDM subgroup with HOMA-IR < 1.61/BMI < 18.5kg/m2 exhibited the highest rates of premature rupture of membrane (46.7%) and postpartum hemorrhage (20%), predominantly with vaginal delivery and a 1min Apgar score of 4.5% in GDM women with HOMA-IR < 1.61/18.5kg/m2 ≤ BMI < 25kg/m2. GDM and its subgroups displayed severe insulin resistance and poorer insulin sensitivity, leading to an increased risk of adverse pregnancy outcomes. GDM women with higher IR and normal or over weight were more likely to experience LGA and macrosomia, while those with lower IR and underweight were prone to premature rupture of membrane and postpartum hemorrhage during vaginal delivery.

Case report: a case of severe insulin resistance due to antibodies specific for detemir

Case report: a case of severe insulin resistance due to antibodies specific for detemir

A Randomized Controlled Trial to Assess the Feasibility and Practicability of an Oatmeal Intervention in Individuals with Type 2 Diabetes: A Pilot Study in the Outpatient Sector.

Background/Objectives: The aim of this study was to investigate the feasibility and practicability of repeated three-day sequences of a hypocaloric oat-based nutrition intervention (OI) in insulin-treated outpatients with type 2 diabetes and severe insulin resistance. Methods: A randomized, two-armed pilot study was conducted with three months of intervention and three months follow-up with 17 participants with insulin resistance (≥1 IU/kg body weight). Group A (n = 10) performed one sequence of OI; Group B (n = 7) performed two sequences monthly. A sequence was 3 consecutive days of oat consumption with approximately 800 kcal/d. The main objective was to assess feasibility (≥70% completers) and practicability regarding performance aspects. Biomedical parameters such as HbA1 c were observed. To evaluate the state of health, a standardized questionnaire was used (EQ-5 D). Results: OI was feasible (13/17 completer participants (76.5%): 70.0% Group A, 85.7% Group B). Individually perceived practicability was reported as good by 10/16 participants (62.5%). Total insulin dosage decreased from 138 ± 35 IU at baseline to 126 ± 42 IU after OI (p = 0.04) and 127 ± 42 IU after follow-up (p = 0.05). HbA1 c was lower after OI (-0.3 ± 0.1%; p = 0.01) in all participants. Participants in Group B tended to have greater reductions in insulin (Δ-19 IU vs. Δ-4 IU; p = 0.42) and weight loss (Δ-2.8 kg vs. Δ-0.2 kg; p = 0.65) after follow-up. Severe hypoglycemia was not observed. EQ-5 D increase not significantly after follow-up (57.2 ± 24.0% vs. 64.7 ± 21.5%; p = 0.21). Conclusions: The feasibility and practicability of OI in outpatients were demonstrated. OI frequency appears to correlate with insulin reduction and weight loss. Proper insulin dose adaptation during OI is necessary. Presumably, repeated OIs are required for substantial beneficial metabolic effects.

Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

The impact of type 2 diabetes on polycystic ovary syndrome in patients undergoing sleeve gastrectomy.

Does the concurrent type 2 diabetes mellitus (T2DM) aggravate the features and prognosis of PCOS in patients undergoing sleeve gastrectomy (SG)? For patients undergoing SG with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Women with T2DM have an increased risk of PCOS. However, whether concurrent T2DM further increases the disease burden and treatment difficulty of PCOS in patients with obesity requires further investigation. This was a single-center, two-arm, prospective, cohort study enrolling a total of 329 women with PCOS and scheduled for SG because of obesity at an university-affiliated hospital between January 2020 and August 2023, with a 1-year follow-up after surgery. Comparisons were made between patients with T2DM (PCOS+T2DM) and without (PCOS) to examine the impact of T2DM on the metabolic, reproductive, and psychological features of PCOS. The follow-up data of weight loss and menstruation were analyzed to determine the impact of T2DM on PCOS prognosis for up to 1 year after SG. After controlling for confounders, patients in the PCOS+T2DM group (n = 98) showed more severe insulin resistance, glucose intolerance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) (NAFLD activity score 4.31 ± 1.15 versus 3.52 ± 1.42, P < 0.001) than those in the PCOS group (n = 149). In addition, the PCOS+T2DM group had a lower level of total testosterone (1.63 ± 0.69 versus 1.82 ± 0.76, P = 0.045), a lower ratio between luteinizing hormone and follicle-stimulating hormone (median 1.48 versus 1.68, P = 0.030), and a lower proportion of patients with polycystic ovarian morphology (88% versus 96%, P = 0.022) than the PCOS group. As a result, the two groups differed significantly in terms of the Rotterdam classification of PCOS (P = 0.009). No significant difference was detected by group in the psychological features of PCOS except a lower degree of emotional eating in the PCOS+T2DM group (P = 0.001). Although the PCOS+T2DM group took longer to resume regular menstruation after SG (P = 0.037), the two groups had similar proportions of patients with regular menstruation (85% versus 87%, P = 0.758) 1 year after SG, which was further confirmed by subgroup analyses by body mass index. The prognosis of PCOS after SG mainly focused on the results of menstruation rather than a complete evaluation of the remission of the disease. Our study showed that, for patients with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Our study also highlights the need for high-quality studies with a more comprehensive evaluation of the impact of T2DM on the prognosis of patients with PCOS after SG. This study was funded by the National Natural Science Foundation of China Grants (82100853), the Natural Science Foundation of Shandong Province of China (ZR2021QH028), and the Clinical Research Project of Shandong University (2020SDUCRCC024). The authors have no conflicts of interest. Chinese Clinical Trial Registry with No. ChiCTR1900026845.

Relationship of insulin resistance with microvascular and macrovascular complications, death rate and other factors in patients with type 2 diabetes: A case-control study

Abstract: There is a lack of studies analyzing Severe Insulin Resistance (SIR) forms, especially from clinical aspects. The main objective of this research was to assess the relationship between micro- and macrovascular complications and the death rate of patients with SIR. Methods: It was a partially prospective case-control study of 120 participants with T2DM. Patients with doses of insulin &gt;1 IU/kg/day were considered to have SIR (case group), with an insulin requirement of &lt;1 IU/kg/day - control group. Statistical analyses were performed. Results: Regarding microvascular complications, an association was found between insulin doses and the rate of Diabetic Nephropathy (DN) in the case group compared with the control group (138 vs. 170 IU/day), p = 0.002. Men with T2DM and SIR were more likely to present with myocardial infarction than women (39.3% vs. 13.3%); p = 0.036. Subjects of the case group with lower eGDR (2.44 vs. 1.35) (or higher insulin resistance) were more likely to suffer a stroke, p = 0.003. Case group males were more likely than females to undergo coronary artery bypass graft surgery (21.4% vs. 3.3%); p = 0.048. Higher mortality was observed in the case group of patients with lower eGDR (1.01 vs. 1.85); p = 0.031. Conclusion: As for microvascular outcomes, the rate of DP and DR was similar in both control and case groups. Only the rate of DN in the case group was associated with higher insulin doses. Macrovascular complications such as stroke, myocardial infarction, and bypass surgery were related to the male gender and SIR, as well as higher mortality according to eGDR.

Hereditary Severe Insulin-resistance Syndrome and Acanthosis Nigricans Caused by Novel Mutations in the INSR Gene.

Most cases associated with Hereditary Severe Insulin Resistance Syndrome (H-SIRS) are linked to mutations in the insulin receptor (INSR) gene. Patients with H-SIRS typically manifest symptoms of hyperinsulinemia, insulin resistance, and diabetes mellitus. Other symptoms include impaired glucose regulation, hyperandrogenism, and the presence of acanthosis nigricans (AN). In this report, we present two cases of H-SIRS in female children exhibiting various symptoms, such as hyperinsulinemia, fasting hypoglycemia, postprandial hyperglycemia, overweight, fatty liver, hyperandrogenism, and varying degrees of AN. One patient also presented with mental retardation. Gene sequencing identified specific mutations in the INSR gene for both patients: c.2663A > G (p.Tyr888Cys) and c.38_61del (p.Pro13_Ala20del). These mutations have the potential to disrupt the interaction between INSR and insulin, leading to abnormal insulin signaling, insulin resistance, and various clinical manifestations.

Beyond the Obvious: Acanthosis Nigricans as a Clue to the Rare Case of Rabson–Mendenhall Syndrome

Rabson–Mendenhall syndrome (RMS) is a genetic disorder with autosomal recessive inheritance caused by mutations in the insulin receptor (INSR) gene. It is characterized by severe insulin resistance, acanthosis nigricans, skin tags, and growth retardation. Management of this condition is challenging and requires multidisciplinary approach. We present a case report on RMS in a 7-year-old girl who presented with coarse facies, acanthosis nigricans, skin tags, short stature, abdominal distension, and hyperglycemia with hyperinsulinemia. Her genetic analysis revealed a mutation in exon 3 of the INSR gene. The patient is being treated with tablet metformin and is being followed up.

Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients.

Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied. PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for "Rabson-Mendenhall syndrome" or "Black acanthosis hirsutism insulin resistance syndrome." A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations. The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.

2004-LB: Elucidating Causal Genes of Severe Insulin Resistance Diabetes through Polygenic Exploration of Type 2 Diabetes Heterogeneity

2004-LB: Elucidating Causal Genes of Severe Insulin Resistance Diabetes through Polygenic Exploration of Type 2 Diabetes Heterogeneity

Partial lipodystrophy: Clinical presentation and treatment

Lipodystrophic syndromes are acquired or genetic rare diseases, characterized by a generalized or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They are probably underdiagnosed, especially for partial forms. They are characterized by a lack of adipose tissue or a lack of adipose development leading to metabolic disorders associated with often severe insulin resistance, hypertriglyceridemia and hepatic steatosis. In partial forms of lipodystrophy, these mechanisms are aggravated by excess visceral adipose tissue and/or subcutaneous adipose tissue in the upper part of the body. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counseling. Early lifestyle and dietary measures focusing on regular physical activity, and balanced diet avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndromes.

Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically unhealthy lean phenotype in female mice during aging.

Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤4-mo-old), middle aged (10-14-mo-old), and old (≥18-mo-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic-euglycemic clamp procedure (HECP) demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR-γ) in an age-dependent manner. In addition, administration of a PPAR-γ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue, and whole body metabolic function in female mice during aging.NEW & NOTEWORTHY Defective NAD+ metabolism is associated with aging and age-associated metabolic diseases. In the present study, we provided in-depth metabolic assessments in female mice with adipocyte-specific inactivation of a key NAD+ biosynthetic enzyme NAMPT and revealed an unexpected role of adipose tissue NAMPT-NAD+-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue and whole body metabolic health during the aging process.