Progressive Insulin Resistance Research Articles

The influence of lactation on insulin and glucose metabolism, lipid profile, and cytokines in pregnant mares

Glucose metabolism adapts to gestation, resulting in progressive physiological insulin resistance and increased insulin secretion to maintain maternal euglycemia and glucose availability for the developing fetus. These changes can impact mare fertility and maternal and neonatal health. This is the first comparison of body condition, regional adiposity, insulin and glucose dynamics, lipid metabolism, and cytokine production between lactating and non-lactating mares before, during pregnancy, and early postpartum. Twelve pregnancies from 9 broodmares, five nonlactating (NL) and seven lactating (L), were used. Evaluations were performed on the day of ovulation, at 55, 110, 165, 220, 275, and 330 days of gestation (D55, D110, D165, D220, D275, D330) and 21 days postpartum (21pp). Mares in the L group had lower basal insulin and glucose at the beginning of pregnancy, smaller area under the curve of insulin and glucose, and greater insulin sensitivity and glucose tolerance. Resistin was higher in D110 and D165 than in D0, D275, 330 and 21pp, while leptin was higher in D55, and in D110, at D110 it was equal to D0, D220, and D275, but higher than at D330 and D21pp. As for the groups, L presented lower body condition score (BCS), crest neck score (CNS), rump fat thickness (RUM), basal insulin, glucose area under the curve (AUCg), MIRG and higher RISQI, adiponectin and tumor necrosis factor (TNFα). There was no effect over time in non-esterified fatty acids (NEFA) concentrations between the L mares; in the NL, D275 presented higher concentrations than those of D0, D55, and D110, which in turn were equal to the other time points; there were higher concentrations in NL mares than L in samples D165 and D275. In conclusion, a different metabolic profile during pregnancy was detected, and NL mares were closer to the metabolic threshold for the occurrence of metabolic syndrome during pregnancy. Understanding the impacts of these differences on mare's health and their offspring's future is fundamental as most of our recipient mares for embryo transfer are non-lactating. Therefore, we suggest that further studies be performed to evaluate lactation's influence on mares' metabolic parameters.

Oral glucose tolerance test in pregnancy: questions and answers

Gestational diabetes mellitus (GDM) is one of the most common diseases during pregnancy and increases risks of shortand long-term complications to both mothers and their children. Timely treatment of GDM significantly reduces the specified risks. The development of insulin resistance in pregnancy is associated with increased secretion of maternal and fetoplacental hormones (placental lactogen, estrogens and progesterone, cortisol and prolactin) with increasing gestational age. Thus, GDM develops during pregnancy in patients with insufficient pancreatic function due to progressive hyperglycemia and insulin resistance. Oral glucose tolerance test (OGTT) is the most commonly used test in world practice to establish a diagnosis. In Russia, OGTT is carried out at a gestational age of 24–28 weeks using 75 g of glucose and assessing venous plasma glycemia values at three points: before and 30, 60, and 120 minutes after drinking the glucose solution. However, refusal of patients to complete the test is one of the problems associated with the OGTT. Nausea and vomiting are the most commonly reason for not completing the OGTT. In some cases, patients cannot complete the test due to severe tolerance to a hyperosmolar glucose solution. In such cases, a number of solutions are discussed in the literature, one of which is the possible use of glucose-based compositions comprising flavouring additives, which are allowed for use during pregnancy to improve the tolerability of the OGTT. Improving the tolerability and compliance with the procedure is one of the most important conditions for successful and timely diagnosis.

Insulin induces bioenergetic changes and alters mitochondrial dynamics in podocytes.

Diabetic nephropathy (DN) is one of the most frequent complications of diabetes. Early stages of DN are associated with hyperinsulinemia and progressive insulin resistance in insulin-sensitive cells, including podocytes. The diabetic environment induces pathological changes, especially in podocyte bioenergetics, which is tightly linked with mitochondrial dynamics. The regulatory role of insulin in mitochondrial morphology in podocytes has not been fully elucidated. Therefore, the main goal of the present study was to investigate effects of insulin on the regulation of mitochondrial dynamics and bioenergetics in human podocytes. Biochemical analyses were performed to assess oxidative phosphorylation efficiency by measuring the oxygen consumption rate (OCR) and glycolysis by measuring the extracellular acidification rate (ECAR). mRNA and protein expression were determined by real-time polymerase chain reaction and Western blot. The intracellular mitochondrial network was visualized by MitoTracker staining. All calculations were conducted using CellProfiler software. Short-term insulin exposure exerted inhibitory effects on various parameters of oxidative respiration and adenosine triphosphate production, and glycolysis flux was elevated. After a longer time of treating cells with insulin, an increase in mitochondrial size was observed, accompanied by a reduction of expression of the mitochondrial fission markers DRP1 and FIS1 and an increase in mitophagy. Overall, we identified a previously unknown role for insulin in the regulation of oxidative respiration and glycolysis and elucidated mitochondrial dynamics in human podocytes. The present results emphasize the importance of the duration of insulin stimulation for its metabolic and molecular effects, which should be considered in clinical and experimental studies of DN.

A comparative study of efficacy and safety of glimepiride versus gliclazide as an add on to metformin in Type 2 diabetes mellitus at a tertiary care hospital

Background: Type 2 diabetes mellitus (T2DM) is a chronic disorder with progressive pancreatic β-cell dysfunction and insulin resistance. Hyperglycemia associated with uncontrolled T2DM leads to various diabetes-related complications. Although metformin is the most preferred first-line drug, 5–10% of patients per year subsequently fail to achieve target HbA1c levels, subsequently requiring combination therapy. While efficacy and cost favor the use of sulfonylureas, hypoglycemic episodes limit its use. Newer generation sulfonylureas such as glimepiride and gliclazide are presumed to have lower incidence of hypoglycemia. Aims and Objectives: The aim of the study was to assess the efficacy and safety of glimepiride versus gliclazide as an add-on to metformin in T2DM. Materials and Methods: A total of 60 patients with T2DM (HbA1c 7.0–10.0%, on metformin monotherapy) were recruited and randomized into two groups of 30 cases each. Group A received glimepiride 2 mg as add-on to metformin 1500 mg and Group B received gliclazide 80 mg as add-on to metformin 1500 mg. HbA1c, lipid profile, body mass index, and total blood count were assessed at baseline and at the end 12 weeks of treatment. Fasting blood sugar (FBS) and post prandial blood sugar (PPBS) were assessed at the end of 4, 8, and 12 weeks and adverse events were assessed throughout the study period. Results: There was a significant decrease in HbA1c, FBS, and PPBS scores from baseline to the end of 12 weeks in both groups (P < 0.001), but the difference was not statistically significant between the two groups (P > 0.05). A significant decrease in lipid levels was observed in both groups except for high-density lipoprotein, low-density lipoprotein in the metformin + gliclazide group. The treatment was well tolerated in both groups, with the most common adverse events being nausea, diarrhea, and epigastric pain. Conclusion: Glimepiride and gliclazide are both equally effective as an add-on to metformin in improving glycaemic indices and are well tolerated in the management of uncontrolled T2DM.

Body Composition Changes Impact Islet β-Cell Function in Patients With Type 2 Diabetes Mellitus.

Background: Identifying β-cells dysregulation in type 2 diabetes mellitus (T2DM) is crucial. Weight fluctuations are frequently observed during diabetes treatment. However, the relationship between body composition changes and islet β-cell function in individuals with T2DM remains insufficiently investigated. Methods: This retrospective longitudinal study encompassed a cohort of 775 T2DM patients, who underwent body composition measuring using dual-energy X-ray absorptiometry (DEXA) and followed up for a median of 2.29 years. Key metrics included body mass index (BMI), fat mass index (FMI), trunk fat mass index (TFMI), muscle mass index (MMI), appendicular skeletal muscle mass index (ASMI), muscle/fat mass ratio (M/F), and the appendicular skeletal muscle mass/trunk fat mass ratio (A/T) were then categorized and grouped. Insulin, C-peptide, and glucose levels were assessed concurrently following a glucose load. β-cell function included insulin resistance (HOMA-IR), insulin sensitivity (Matsuda index (MI)), and insulin secretion evaluated by HOMA-β and C-peptidogenic index (CGI). Results: Although no significant changes in BMI were observed, patients with T2DM at readmission exhibited higher FMI, TFMI, and ASMI, as well as elevated levels of HOMA-IR, MI, and CGI compared to baseline measurements. And lower MI, higher levels of CGI, and HOMA-IR were observed in BMI increased group. Univariate correlation analysis revealed a negative association between changes in BMI (ΔBMI) and ΔMI, while positive associations were observed in both ΔHOMA-IR and ΔCGI. Among body composition indexes, ΔFMI exhibited the strongest correlation with ΔHOMA-IR (r = 0.255, p < 0.001), and ΔASMI was positively associated with ΔMI and ΔCGI (r = 0.131 and 0.194, respectively). Moreover, increased levels of BMI and FMI were associated with a greater risk of progressive insulin resistance compared to the decreased, whereas the trend was converse in ASMI and A/T. Conclusions: Increased FMI may partially contribute to the deterioration of insulin resistance, while increased ASMI is associated with improved insulin sensitivity and secretion. Maintaining an appropriate BMI and muscle/fat ratio is conductive to prevent the progression of insulin resistance in patients with T2DM.

The role of adipose tissue and subsequent liver tissue hypoxia in obesity and early stage metabolic dysfunction associated steatotic liver disease.

Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia. Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L-amino acid defined high-fat diet (CDAHFD). HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD. Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.

THU026 Severe Insulin Resistance In Type 1 Diabetes Due To Growth Hormone Producing Pituitary Macroadenoma

Abstract Disclosure: R. Pansare: None. D. Khurram: None. L. Folsom: None. Background: Acromegaly is a rare disorder with an incidence ranging from 28 to 137 per million. Elevated IGF-1 in acromegaly is associated with severe insulin resistance and diabetes mellitus in the absence of visceral adiposity. We present a case of acromegaly identified in a lean individual with type 1 diabetes with progressive, severe insulin resistance requiring U-500 insulin via insulin pump. Clinical Case: A 28-year-old individual with type 1 diabetes mellitus diagnosed at age 17 years, hyperlipidemia, PCOS, rheumatoid arthritis, depression, and fibromyalgia presented with symptoms of brain fog, fatigue, functional decline, and nocturnal hyperhidrosis. Vital signs obtained in endocrinology clinic revealed blood pressure 100/70 mmHg and BMI 27 kg/m2. Glycemic control was suboptimal with HbA1c ranging from 7.5-9.5% over the past 2 years. The patient had developed progressive insulin resistance with subsequently increased insulin needs, ultimately requiring U-500 insulin administered via insulin pump. Brain MRI ordered due to additional symptoms revealed a sellar mass. Dedicated pituitary MRI confirmed a 2.1 cm anterior pituitary macroadenoma with compression of the optic chiasm, without cavernous sinus invasion. Biochemical evaluation at 9:57am revealed elevated IGF-1 801 ng/ml (93 - 297), Z-score +5.1. Additional testing revealed ACTH 17.9 pg/ml (7.2 - 63.3), cortisol 9.6 mcg/dl (3.7 - 19.4), TSH 0.741 mIU/L (0.27 - 4.2), free T4 1.32 ng/dl (0.93 - 1.7), prolactin 8.4 ng/ml (5.2 - 26.5), leptin 14.4 ng/ml (0.5 - 15.2), LDL 151 mg/dl (0 - 100), triglycerides 203 mg/dl (0 - 149). The patient subsequently underwent transsphenoidal resection of the pituitary macroadenoma. Discussion: Diabetes mellitus in acromegaly is associated with increased mortality. When elevated, IGF-1 level has been shown to be an independent predictor for risk of development of diabetes mellitus in acromegaly and correlates with insulin resistance. A unique challenge arises when the diagnosis of acromegaly is suspected in existing uncontrolled diabetes, as IGF-1 levels may be elevated, normal, or low. Post-surgical reduction in serum IGF-1 level is associated with early postoperative improvement in glucose tolerance. As such, once the diagnosis is confirmed, prompt surgical intervention is imperative to decrease this risk, as well as to improve hyperglycemia and decrease insulin requirements. Although de novo type 2 diabetes in acromegaly is common, our case is novel as it highlights the need to expand the differential diagnosis to include exogenous causes for progressively worsening insulin resistance in individuals with type 1 diabetes. Presentation: Thursday, June 15, 2023

Metformin and its redox-related mechanisms of action in type 2 diabetes

Type 2 diabetes (T2D) is a long-term metabolic disease characterized by progressive β-cell functional decline and insulin resistance, which increases the risk of cardiovascular complications as well as associated-morbidity and mortality. Evidence suggests a strong relationship between hyperglycaemia, oxidative stress and the development and progression of T2D. Indeed, a hyperglycaemic state can reduce the activity of antioxidant enzymes and increase lipid peroxidation and protein oxidation products, as well as DNA damage. At present, metformin is the recommended first-line glucose-lowering agent in patients with T2D. Despite the vast clinical experience gained over several decades of use, several mechanisms of action of metformin have yet to be fully elucidated. This review provides an overview of the existing literature concerning the complicated interplay between oxidative stress and T2D and the molecular mechanisms underlying the redox-related mechanisms of action of metformin, which include (but are not limited to) interaction with AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms, inhibition of gluconeogenesis and action on leukocyte–endothelium interactions.

A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization's Role as a Treatment Modality.

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

265-LB: Human Skeletal Muscle Mitochondrial Dynamics across the Insulin-Sensitivity Spectrum

Introduction: There is immense dispute as to whether perturbations in skeletal muscle mitochondrial function contribute to the onset and progression of type 2 diabetes (T2D). The purpose of this study was to examine differences in mitochondrial dynamics, structure, and energetic function in humans across the spectrum of insulin sensitivity. Methods: 58 sedentary adults (37±12 years) were enrolled into one of three groups based upon the following criteria: (1) healthy weight without T2D (HW; BMI: 22.6±1.8 kg/m2 and HbA1c: 5.0±1.1 %); (2) overweight/obesity without T2D (Ov/Ob; BMI: 32.6±3.3 kg/m2 and HbA1c: 5.6±0.4 %); or (3) overweight/obesity with T2D (T2D; BMI: 36.1±6.5 kg/m2 and HbA1c: 6.9±0.9 %). Participants underwent a 3-day inpatient stay consisting of body composition (DXA), aerobic capacity (VO2MAX), and insulin sensitivity (hyperinsulinemic euglycemic clamp). Prior to insulin sensitivity testing, a skeletal muscle biopsy was obtained for determination of mitochondrial dynamics (Western blot), DNA content (qPCR), ultrastructure (electron microscopy), and respiratory capacity (respirometry). Comparisons were made using a one-way ANOVA with contrasts. Results: Insulin sensitivity and aerobic capacity were lower in Ov/Ob and T2D compared to HW. Markers of mitochondrial fission were higher in T2D (Drp1Ser616, MiD49), and fusion lower in T2D and Ov/Ob (Mfn2). The mitophagy marker Parkin was higher in T2D only while Pink1 was lower in T2D relative to Ov/Ob but not HW. The autophagy marker LC3II was higher in Ov/Ob. Mitochondrial content was lower in Ov/Ob and T2D relative to HW. Mitochondrial respiratory capacity was similar between groups. Conclusions: T2D is associated with heightened expression of proteins required for mitochondrial quality control and reduced mitochondrial volume despite intact respiratory function. These data support the notion that mitochondria adapt to progressive insulin resistance by increasing fragmentation to maintain bioenergetic capacity. Disclosure C. L. Axelrod: None. C. Fealy: Employee; Mission Therapeutics. C. L. Hoppel: None. J. P. Kirwan: None. W. S. Dantas: None. E. R. M. Zunica: None. K. Belmont: None. E. C. Heintz: None. G. Davuluri: None. J. T. Mey: None. M. Erickson: None. H. Fujioka: None. Funding National Institutes of Health (DK108089, GM104940)

Effect of Vitamin D Supplementation on Serum 25-Hydroxyvitamin D and Homeostatic Model of Insulin Resistance Levels in Healthy Pregnancy: A Systematic Review and Meta-Analysis.

Progressive insulin resistance is a physiological condition during pregnancy that can lead to gestational diabetes. Given the association between low blood vitamin D levels and insulin resistance, the present meta-analysis evaluated the effect of vitamin D supplementation on serum 25-hydroxyvitamin D (25[OH]D) and the homeostatic model of insulin resistance (HOMA-IR) levels in non-diabetic pregnant women. A comprehensive literature search was conducted using electronic databases and gateways such as Cochrane Library, Medline, Google Scholar, Science Direct, Web of Sciences, Embase, and Scopus. Articles up to 2020 in both English and Persian were included in the study. The effect of vitamin D supplementation on 25(OH)D and HOMA-IR was determined based on the differences in mean changes from baseline to post-intervention. Weighted mean and 95% confidence intervals (CI) were pooled using a random-effects model. Data were analyzed using STATA software. Four studies, including six trials with 380 participants, reported that vitamin D supplementation increased 25(OH)D (mean change: 13.72, 95% CI: 7.28-20.17) and decreased HOMA-IR (mean change: 1.46, 95% CI: 0.56-2.37) levels compared with the placebo group. A high weekly dose of vitamin D further reduced HOMA-IR levels (adjusted R2=77.99, I2 residuals=80.49%, P=0.047). There was no significant association between the dose of vitamin D and 25(OH)D (P=0.974). Intervention duration was not associated with an increase in 25(OH)D (P=0.102), nor with a decrease in HOMA-IR (P=0.623). Vitamin D supplementation increased 25(OH)D and decreased HOMA-IR levels in non-diabetic pregnant women. Vitamin D in high doses further reduced HOMA-IR, but did not affect 25(OH)D concentrations.

Naringin Ameliorates Skeletal Muscle Atrophy and Improves Insulin Resistance in High-Fat-Diet-Induced Insulin Resistance in Obese Rats.

Obesity causes progressive lipid accumulation and insulin resistance within muscle cells and affects skeletal muscle fibres and muscle mass that demonstrates atrophy and dysfunction. This study investigated the effects of naringin on the metabolic processes of skeletal muscle in obese rats. Male Sprague Dawley rats were divided into five groups: the control group with normal diet and the obese groups, which were induced with a high-fat diet (HFD) for the first 4 weeks and then treated with 40 mg/kg of simvastatin and 50 and 100 mg/kg of naringin from week 4 to 8. The naringin-treated group showed reduced body weight, biochemical parameters, and the mRNA expressions of protein degradation. Moreover, increased levels of antioxidant enzymes, glycogen, glucose uptake, the expression of the insulin receptor substrate 1 (IRS-1), the glucose transporter type 4 (GLUT4), and the mRNA expressions of protein synthesis led to improved muscle mass in the naringin-treated groups. The in vitro part showed the inhibitory effects of naringin on digestive enzymes related to lipid and glucose homeostasis. This study demonstrates the potential benefits of naringin as a supplement for treating muscle abnormalities in obese rats by modulating the antioxidative status, regulating protein metabolism, and improved insulin resistance in skeletal muscle of HFD-induced insulin resistance in obese rats.

Overexpression of TRIM32 promotes pancreatic β-cell autophagic cell death through Akt/mTOR pathway under high glucose conditions.

Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic and is characterized by progressive pancreatic β-cell dysfunction and insulin resistance. Tripartite motif protein 32 (TRIM32) belongs to the TRIM family protein and has been shown to be involve in insulin resistance in skeletal muscle and the liver. However, the effect of TRIM32 on pancreatic β-cell dysfunction and its mechanism remains unknown. In the current study, we found that serum TRIM32 concentrations of T2DM in patients were significantly elevated compared to those in healthy controls, which indicated that TRIM32 might be used as a diagnostic biomarker in T2DM patients. In INS-1 cells, exposure to high glucose (HG) conditions caused a significant elevation in TRIM32 expression and TRIM32 was located in the nucleus. Overexpression of TRIM32 in INS-1 cells exacerbated the effects of HG-induced autophagy and impaired insulin secretion. In contrast, the silencing of TRIM32 produced the opposite effect. Furthermore, TRIM32 overexpression decreased the phosphorylation levels of Akt and mTOR under HG conditions. However, the activation of Akt/mTOR by MHY1485 reversed the effects of TRIM32 on HG-treated INS-1 cells. Collectively, the present results suggested that TRIM32 participates in the development of T2DM by modulating autophagic cell death and insulin secretion, which might occur through the Akt/mTOR pathway. Thus, TRIM32 might be a promising target in T2DM therapy.

Dysregulated insulin secretion is associated with pancreatic β-cell hyperplasia and direct acinar-β-cell trans-differentiation in partially eNOS-deficient mice.

eNOS‐deficient mice were previously shown to develop hypertension and metabolic alterations associated with insulin resistance either in standard dietary conditions (eNOS−/− homozygotes) or upon high‐fat diet (HFD) (eNOS+/− heterozygotes). In the latter heterozygote model, the present study investigated the pancreatic morphological changes underlying the abnormal glycometabolic phenotype. C57BL6 wild type (WT) and eNOS+/− mice were fed with either chow or HFD for 16 weeks. After being longitudinally monitored for their metabolic state after 8 and 16 weeks of diet, mice were euthanized and fragments of pancreas were processed for histological, immuno‐histochemical and ultrastructural analyses. HFD‐fed WT and eNOS+/− mice developed progressive glucose intolerance and insulin resistance. Differently from WT animals, eNOS+/− mice showed a blunted insulin response to a glucose load, regardless of the diet regimen. Such dysregulation of insulin secretion was associated with pancreatic β‐cell hyperplasia, as shown by larger islet fractional area and β‐cell mass, and higher number of extra‐islet β‐cell clusters than in chow‐fed WT animals. In addition, only in the pancreas of HFD‐fed eNOS+/− mice, there was ultrastructural evidence of a number of hybrid acinar‐β‐cells, simultaneously containing zymogen and insulin granules, suggesting the occurrence of a direct exocrine‐endocrine transdifferentiation process, plausibly triggered by metabolic stress associated to deficient endothelial NO production. As suggested by confocal immunofluorescence analysis of pancreatic histological sections, inhibition of Notch‐1 signaling, likely due to a reduced NO availability, is proposed as a novel mechanism that could favor both β‐cell hyperplasia and acinar‐β‐cell transdifferentiation in eNOS‐deficient mice with impaired insulin response to a glucose load.

NEONATAL OUTCOMES IN GESTATIONAL DIABETES MELLITUS

Background: Gestational diabetes mellitus (GDM) is a common and serious maternal complication, in which hyperglycemia develops at any time during pregnancy due to progressive insulin resistance. It affects about 14% of pregnancies worldwide. There are many adverse effects of GDM that compromise the fetus and neonate. Objective: To compare neonatal outcomes according to type of treatment for GDM. Methods: A prospective study conducted at the Department of Pediatrics, (Neonatal Intensive Care Unit; NICU) and Obstetric in Al-Imamein Al-Kadhimein Medical City in Baghdad during a period from 1st of march 2019 to 1st of January 2020. The study included 100 neonates delivered by mothers with GDM, divided in to four groups according to their mothers' therapy; (diet group: 18 neonates, metformin group: 36, insulin group: 26, mixed group: 20). Results: Neonates in metformin group had a higher chance of having normal birth weight comparing with others, but neonates in insulin group have higher percent of prematurity, macrosomia, large for gestational age or small for gestational age, hypoglycemia and jaundice among others. No significant statistical difference between metformin and insulin, in mode of delivery, Apgar score, respiratory distress syndrome, hypocalcaemia, anomalies, and NICU admission but can occur more in insulin group. Conclusion: Metformin was able to reduce the risk of neonatal complications, therefore, it can be a good alternative for insulin in the treatment of GDM. Keywords: Gestational diabetes mellitus, macrosomia, metformin, insulin Citation: Rashed GM, Al-Omrani AA, Mohmmed ZA, Al-Bahadle AJ. Neonatal outcomes in gestational diabetes mellitus. Iraqi JMS. 2022; 20(1): 59-67. doi: 10.22578/IJMS.20.1.8

Sodium, Glucose and Dysregulated Glucagon Secretion: The Potential of Sodium Glucose Transporters.

Diabetes is defined by hyperglycaemia due to progressive insulin resistance and compromised insulin release. In parallel, alpha cells develop dysregulation of glucagon secretion. Diabetic patients have insufficient glucagon secretion during hypoglycaemia and a lack of inhibition of glucagon secretion at higher blood glucose levels resulting in postprandial hyperglucagonaemia, which contributes to the development of hyperglycaemia. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an efficient pharmacologic approach for the treatment of hyperglycaemia in type 2 diabetes. While SGLT2 inhibitors aim at increasing glycosuria to decrease blood glucose levels, these inhibitors also increase circulating glucagon concentrations. Here, we review recent advances in our understanding of how SGLTs are involved in the regulation of glucagon secretion. Sodium plays an important role for alpha cell function, and a tight regulation of intracellular sodium levels is important for maintaining plasma membrane potential and intracellular pH. This involves the sodium-potassium pump, sodium-proton exchangers and SGLTs. While the expression of SGLT2 in alpha cells remains controversial, SGLT1 seems to play a central role for alpha cell function. Under hyperglycaemic conditions, SGLT1 mediated accumulation of sodium results in alpha cell dysregulation due to altered cellular acidification and ATP production. Taken together, this suggests that SGLT1 could be a promising, yet highly underappreciated drug target to restore alpha cell function and improve treatment of both type 1 and 2 diabetes.

Obesity as a risk factor for diseases of the digestive system

Currently, the global prevalence of obesity among the worlds adult population is about 650 million people, which makes it possible to consider this chronic metabolic disease as a non-infectious pandemic of the 21st century. It has been proven that obesity is associated with several gastroenterological diseases, while the mechanisms of these associations are extremely heterogeneous and multifactorial. Hypertrophy and hyperplasia of adipocytes in obesity lead to a change in the profile of adipokine production (a decrease in adiponectin, an increase in leptin), an increase in the production of pro-inflammatory cytokines (interleukin-1, 6, 8, tumor necrosis factor ), C-reactive protein, free fatty acids, as well as active forms of oxygen (superoxide radicals, H2O2). All the above induces the development of chronic slowly progressive inflammation, oxidative stress, and insulin resistance. In addition, peptides secreted by adipocytes (adiponectin, leptin, nesfatin-1 and apelin) can modulate gastrointestinal motility, acting both centrally and peripherally. The qualitative and quantitative changes in the intestinal microbiota observed in obese patients (increased Firmicutes and decreased Bacteroidetes) lead to a decrease in the production of short-chain fatty acids and an increase in the intestinal permeability due to disruption of intercellular tight junctions, which leads to increased translocation of bacteria and endotoxins into the systemic circulation. Numerous studies have demonstrated the association of obesity with diseases of the esophagus (gastroesophageal reflux disease, Barretts esophagus, esophageal adenocarcinoma, esophageal motility disorders), stomach (functional dyspepsia, stomach cancer), gallbladder (cholelithiasis, gallbladder cancer), pancreas (acute pancreatitis, pancreatic cancer), liver (non-alcoholic fatty liver disease, hepatocellular carcinoma), intestine (diverticular disease, irritable bowel syndrome, colorectal cancer).

Case Series: Reversal of Diabetic Neuropathy Utilizing Physiologic Insulin Resensitization

Diabetes is a growing global problem that is currently on the rise. Type 2 diabetes (T2D) is a chronic condition that results from aberrant B-cell function coupled with progressive insulin resistance. The majority of Type 2 diabetic patients develop diabetic neuropathy, which can lead to devastating complications (i.e., infection, ulceration, osteomyelitis, &amp; amputation). The proinflammatory state of diabetes, along with prolonged hyperglycemia damages peripheral nerves (most common in the lower extremities). Additionally, compromised wound healing exacerbates the risk when skin breakdown occurs in this patient population. To overcome these risks for T2D, physiologic insulin resensitization (PIR) has been used as a novel protocol to treat patients with severe neuropathy symptoms. In our case study, we present two patients who initially experienced a loss of sensation in their extremities and decreased wound healing. Using PIR treatment, we demonstrate that both patients experienced neuropathy reversal and improved wound healing.

Timing of acute passive heating on glucose tolerance and blood pressure in people with type 2 diabetes: a randomized, balanced crossover, control trial.

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to the following three conditions: 1) 3-h OGTT (control), 2) 1-h passive heating (40°C water) 30 min before an OGTT (HOT-OGTT), and 3) 1-h passive heating (40°C water) 30 min after commencing an OGTT (OGTT-HOT). Blood glucose concentration, insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood glucose concentration [control: 1,677 (386) arbitrary units (AU), HOT-OGTT: 1,797 (340) AU, and OGTT-HOT: 1,662 (364) AU, P = 0.28], insulin sensitivity (P = 0.15), or SBP (P = 0.18) but did increase eHSP70 concentration in both heating conditions [control: 203.48 (110.81) pg·mL-1; HOT-OGTT: 402.47 (79.02) pg·mL-1; and OGTT-HOT: 310.00 (60.53) pg·mL-1, P < 0.001], increased TEE (via fat oxidation) in the OGTT-HOT condition [control: 263 (33) kcal, HOT-OGTT: 278 (40) kcal, and OGTT-HOT: 304 (38) kcal, P = 0.001], increased HR in both heating conditions (P < 0.001), and reduced DBP in the OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase eHSP70 concentration and TEE and reduce blood pressure in people with T2DM.NEW & NOTEWORTHY This is the first study to investigate the timing of acute passive heating on glucose tolerance and extracellular heat shock protein 70 concentration ([eHSP70]) in people with type 2 diabetes. The principal novel findings from this study were that both passive heating conditions: 1) did not reduce the area under the curve or peak blood glucose concentration, 2) elevated heart rate, and 3) increased [eHSP70], which was blunted by glucose ingestion, while passive heating following glucose ingestion, 4) increased total energy expenditure, and 5) reduced diastolic blood pressure.

Adipose stem cells in obesity: challenges and opportunities.

Adipose tissue, the storage of excessive energy in the body, secretes various proteins called adipokines, which connect the body’s nutritional status to the regulation of energy balance. Obesity triggers alterations of quantity and quality of various types of cells that reside in adipose tissue, including adipose stem cells (ASCs; referred to as adipose-derived stem/stromal cells in vitro). These alterations in the functionalities and properties of ASCs impair adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance, and other metabolic disorders. In contrast, the ability of ASCs to recruit new adipocytes when faced with caloric excess leads to healthy adipose tissue expansion, associated with lower amounts of inflammation, fibrosis, and insulin resistance. This review focuses on recent advances in our understanding of the identity of ASCs and their roles in adipose tissue development, homeostasis, expansion, and thermogenesis, and how these roles go awry in obesity. A better understanding of the biology of ASCs and their adipogenesis may lead to novel therapeutic targets for obesity and metabolic disease.