Insulin-treated Group Research Articles

Effects of insulin and analogues on carcinogen-induced mammary tumours in high-fat-fed rats.

It is not fully clarified whether insulin glargine, an analogue with a high affinity for insulin-like growth factor-1 receptor (IGF-1R), increases the risk for cancers that abundantly express IGF-1R such as breast cancer or some types of breast cancer. To gain insight into this issue, female Sprague–Dawley rats fed a high-fat diet were given the carcinogen N-methyl-N-nitrosourea and randomly assigned to vehicle (control), NPH (unmodified human insulin), glargine or detemir (n = 30 per treatment). Insulins were given subcutaneously (15 U/kg/day) 5 days a week. Mammary tumours were counted twice weekly, and after 6 weeks of treatment, extracted for analysis. None of the insulin-treated groups had increased mammary tumour incidence at any time compared with control. At 6 weeks, tumour multiplicity was increased with NPH or glargine (P < 0.05) and tended to be increased with detemir (P = 0.2); however, there was no difference among insulins (number of tumours per rat: control = 0.8 ± 0.1, NPH = 1.8 ± 0.3, glargine = 1.5 ± 0.4, detemir = 1.4 ± 0.4; number of tumours per tumour-bearing rat: control = 1.3 ± 0.1, NPH = 2.2 ± 0.4, glargine = 2.7 ± 0.5, detemir = 2.3 ± 0.5). IGF-1R expression in tumours was lower than that in Michigan Cancer Foundation-7 (MCF-7) cells, a cell line that shows greater proliferation with glargine than unmodified insulin. In rats, glargine was rapidly metabolised to M1 that does not have greater affinity for IGF-1R. In conclusion, in this model of oestrogen-dependent breast cancer in insulin-resistant rats, insulin and insulin analogues increased tumour multiplicity with no difference between insulin types.

Neonatal Hypoglycemia Following Diet-Controlled and Insulin-Treated Gestational Diabetes Mellitus

To assess the risk of neonatal hypoglycemia following diet-controlled and insulin-treated gestational diabetes mellitus (GDM) and how it relates to birth weight. Prospective cohort study included term neonates born after GDM from January 2013 through December 2015 at the University Medical Center Utrecht (Utrecht, the Netherlands). Routine screening of neonatal blood glucose levels was performed at 1, 3, 6, 12, and 24 h after birth. Main outcome measures were neonatal hypoglycemia defined as blood glucose ≤36 mg/dL (severe) and ≤47 mg/dL (mild). A total of 506 neonates were included, born after pregnancies complicated by GDM treated either with insulin (22.5%) or without insulin (77.5%). The incidence of mild and severe hypoglycemia was similar in the insulin-treated and diet-controlled groups (33 vs. 35%, P = 0.66; and 20 vs. 21%, P = 0.79). A birth weight >90th centile was seen in 17.2% of all infants. Although children with a birth weight >90th centile had the highest risk for hypoglycemia, the vast majority of hypoglycemia (78.6%) was detected in those with a birth weight <90th centile. Over 95% of all hypoglycemia occurred within 12 h after birth. Routine screening for neonatal hypoglycemia following pregnancies complicated by GDM reveals high incidence of both mild and severe hypoglycemia for both diet-controlled and insulin-treated GDM and across the full range of birth weight centiles. We propose routine blood glucose screening for neonatal hypoglycemia within the first 12 h of life in all neonates after GDM, irrespective of maternal insulin use or birth weight.

Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11–13-Year-Old Children Born to Women with Gestational Diabetes Mellitus

BackgroundChildren exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. MethodsUsing transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11–13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FindingsGDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. InterpretationThese results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

IGF-1R Inhibitor Ameliorates Diabetic Nephropathy with Suppressed HMGN1/TLR4 Pathway.

This study was established to investigate the contribution of high mobility group nucleosome-binding protein 1 (HMGN1)/ Toll-like receptor 4 (TLR4) pathway in diabetic nephropathy (DN). And as an intervention of the potential mechanism above, the insulin growth factor 1 receptor (IGF-1R) inhibitor was examined for its therapeutic effect in the diabetic mice. Male C57BL/6J mice were administered streptozotocin(STZ) to induce diabetes and thus divided into 5 groups: the untreated group (DN group), the benazepril-treated group (BEN-DN group), the insulin-treated group (INS-DN group) and the IGF-1R inhibitor-treated group (IGF-DN group). Immunohistochemistry and in situ hybrization were performed to detect the expression of HMGN1 and TLR4 in renal tissue. To evaluate the effect of IGF-1R inhibitor, levels of blood glucose and kidney/ body weight (KW/BW) were measured. And morphological changes and mesangial matrix expansion in kidneys were also detected. Increased expression of HMGN1 and TLR4 in renal tissue of STZ-induced type1 diabetic mellitus (T1DM) mice models was observed. IGF-1R inhibitor attenuate the established nephropathy with reduced expression of TLR4 protein, as revealed by a decrease in mesangial index. IGF-1R inhibitor might have therapeutic potential in DN through inhibition of HMGN1/TLR4 pathway.

Safety of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2-I) During the Month of Ramadan in Muslim Patients with Type 2 Diabetes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2-I) are a new class of antidiabetic drugs that might increase the risk of dehydration and hypoglycemia, particularly during the month of Ramadan in which Muslims abstain from eating and drinking for 14-16 hours daily. We aimed to provide real-life evidence about the safety of SGLT2-I during Ramadan. All patients over the age of 18 years on SGLT2-I before Ramadan 2016 who would be fasting during Ramadan were included. Demographic data, detailed medical history including comorbidities and medication profile, and laboratory results were collected before and after Ramadan. We also conducted a phone interview to evaluate the frequency and severity of hypoglycemia and dehydration. Of the total of 417 patients, 113 (27.0%) experienced hypoglycemic events, and 93 of these (82.3%) checked their blood glucose using a glucometer. Confirmed hypoglycemia (< 70 mg/dL) was observed in 78 (83.8%). The hypoglycemic events were significantly more frequent in the SGLT2-I plus insulin-treated group than in those treated with SGLT2-I plus oral hypoglycemic agents group (p < 0.001). Confirmed hypoglycemic events were more frequent in those using SGLT2-I plus intensive insulin compared to those using SGLT2-I plus basal insulin (p = 0.020). Symptoms of dehydration were seen in 9.3% (n = 39) of the total population. We observed statistically significant reductions in glycated hemoglobin and weight by the end of Ramadan (p < 0.001). There were no significant changes in lipid profile and creatinine levels by the end of the study. The use of insulin in combination with SGLT2-I increases the risk of hypoglycemia during Ramadan. Hypoglycemic events were mild and did not require hospital admission. However, careful monitoring during prolonged fasting is warranted. No significant harmful effects on renal function result from treatment with SGLT2-I during Ramadan.

The effects of maternal diabetes and insulin treatment on neurogenesis in the developing hippocampus of male rats

Diabetes in pregnancy is associated with an increasing risk of congenital malformations and central nervous system disorders (CNS) especially hippocampal neuronal circuitry disruption as a discreet region involved in neurogenesis phenomenon. This study aimed to investigate the effect of maternal diabetes and insulin treatment on the expression and distribution pattern of NeuN and DCX as two important markers of neurogenesis paradigm in developing rat hippocampus. All animals were randomly divided into three groups as follows: Control group, Diabetic (STZ-D), Diabetic treated with insulin (STZ-INS). Diabetes was induced in Wistar female rats by Sterptozotocin intraperitoneal injection (single does). Following confirmation of diabetes, animals were mated with non-diabetic males. Four to six units of protamine-Zinc insulin were delivered subcutaneously (SC) in insulin treated group. At the post-natal day 14 (P14), the brain of male offspring’s were removed for further study. In fact Immunofluorescence staining and Real time − PCR assays are used for evaluation of neurogenesis phenomenon. Our results showed a significant higher level of hippocampal DCX expression and an increase in the mean number of DCX positive cells in the DG of diabetic group male offspring (P < 0.05). We also found an insignificant up-regulation in the expression of DCX and the mean number of positive cells in the insulin-treated diabetic group neonates as compared to control group (P > 0.05). Nevertheless the results of immunofluorescence staining for NeuN also indicated that the mean number of NeuN+ cells was significantly lower in dentate gyrus of diabetic group male offspring (P < 0.05). Besides, there were significant down- regulation in the hippocampal mRNA expression of NeuN in diabetic pups compare to control (P < 0.05 each). Our results revealed that diabetes during pregnancy has an adverse effect on the hippocampal neurogenesis in rat neonates. Furthermore, the control of glycemia by insulin is sufficient to prevent the alterations in expression of neurogenesis markers.

Combined treatment with melatonin and insulin improves glycemic control, white adipose tissue metabolism and reproductive axis of diabetic male rats

AimsMelatonin treatment has been reported to be capable of ameliorating metabolic diabetes-related abnormalities but also to cause hypogonadism in rats. We investigated whether the combined treatment with melatonin and insulin can improve insulin resistance and other metabolic disorders in rats with streptozotocin-induced diabetes during neonatal period and the repercussion of this treatment on the hypothalamic-pituitary-gonadal axis. Main methodsAt the fourth week of age, diabetic animals started an 8-wk treatment with only melatonin (0.2 mg/kg body weight) added to drinking water at night or associated with insulin (NHP, 1.5 U/100 g/day) or only insulin. Animals were then euthanized, and the subcutaneous (SC), epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Hypothalamus was collected for gene expression and blood samples were collected for biochemical assays. Key findingsThe treatment with melatonin plus insulin (MI) was capable of maintaining glycemic control. In epididymal (EP) and subcutaneous (SC) adipocytes, the melatonin plus insulin (MI) treatment group recovered the insulin responsiveness. In the hypothalamus, melatonin treatment alone promoted a significant reduction in kisspeptin-1, neurokinin B and androgen receptor mRNA levels, in relation to control group. SignificanceCombined treatment with melatonin and insulin promoted a better glycemic control, improving insulin sensitivity in white adipose tissue (WAT). Indeed, melatonin treatment reduced hypothalamic genes related to reproductive function.

Modulatory Effect of Concomitant Administration of Insulin and Vanadium on Inflammatory Biomarkers in Type 2 Diabetic Rats: Role of Adiponectin.

The aim of this study is to investigate the effect of vanadium and/or insulin on the proinflammatory biomarkers in type 2 diabetes mellitus (T2DM) rat model. Sixty male Sprague Dawley rats were divided into six groups (n = 10). Control group, control vanadium group, T2DM group, insulin-treated diabetic group, vanadium-treated diabetic group, and concomitant insulin and vanadium-treated diabetic group. At the end of the experiment, serum glucose, insulin, lipid profile, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), high sensitivity C reactive protein (hs- CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and adiponectin were measured. Administration of insulin and/or vanadium significantly decreased in the plasma levels of glucose, lipid profile, TNF-α, IL-6, hs-CRP, ICAM-1, and VCAM-1 with significant increase in adiponectin in comparison to the diabetic group. Concomitant administration of insulin and vanadium significantly improved the above measured parameters compared to either insulin or vanadium treatment. Based on our results we can conclude that administration of both vanadium and insulin reduced the low-grade systemic inflammation in T2DM, through reduction of both proinflammatory cytokines and adhesion molecules and increase adiponectin.

Pengaruh Insulin, Jahe dan Kombinasi Keduanya Terhadap Jumlah Sel Trofoblas Rattus Norvegicus Model Diabetes Pragestasional

Diabetes mellitus (DM) is a metabolic disease with characteristics of hyperglycemia that has an effect on increasing morbidity and mortality in the mother. One of the complications of pregestational DM (pGDM) is preeclampsia (PE). The perinatal mortality rate increases 20x in pGDM women with PE complication. Exposure to hyperglycemia causes an increase in oxidative stress that increases apoptosis of trophoblast cells which in turn causes the decrease of proliferation and the number of trophoblastic cells and leads to endothelial dysfunction and hypoxia. The purpose of this study was to distinguish the effect of insulin administration and ginger extract on the number of trophoblast cells of R. norvegicus. This research was an experimental research using post-test only control group design. The population used were pregnant R. norvegicus. The sampling technique was simple random sampling with independent variables are insulin and Z. officinale extract and the dependent variable is the number of trophoblast cells. Data analysis of the number of trophoblast cells used wereKruskal-Wallis and Mann-Whitney test. The result showed that there was a significant difference in the trophoblast cell number with p-value <0,05 (p = 0,001) on positive control with insulin treatment group. The conclusion of this study was the presence of ginger extract can be used as a single therapy or combination with insulin for pregestational diabetes.

Perbedaan Pengaruh Pemberian Insulin dan Ekstrak Zingiber officinale Terhadap Berat Badan Lahir Anak Rattus Norvegicus Model Diabetes Melitus Pragestasional

Diabetes during pregnancy can be divided into pregestational diabetes and gestational diabetes. The risk of fetal Diabetes Mellitus pregestational (DMpG) patients can be either macrosomia or low birth weight. The purpose of this study was to investigate the differences in the administration effect of insulin and Zingiber officinale extract on birth weight of Rattus norvegicus pregestational diabetes mellitus model. This research is an experimental research using post test only control group design. Samples contained 30 pregnant Rattus norvegicus and divided into 5 groups, where K0 (negative control group) and K1 (positive control group) given aquadest 1cc, K2 given insulin 1IU, K3 given ginger extract 500mg/ kg BW, K4 given insulin 1IU and ginger extract 500mg/ kg BW. Treatment was administered during the first 16 days of pregnancy. On the 17th day, the rats were terminated and then the birth weight was measured with the scale. Data analysis using One-way ANOVA test followed by Tamhane test. The results showed that there was a difference of birth weight in the insulin treatment group and ginger extract treatment group (p-value = 0,037 < α =0,05). The conclusion of this study was Zingiber officinale can be used as a single therapy or combination with insulin of Rattus norvegicus pregestational diabetes mellitus model.

Clinical, histopathological and immunohistochemical evaluation of the effects of topical NPH-insulin on full-thickness open wounds: an in vivo study in diabetic and non-diabetic mice

In diabetic patients, wound healing is disrupted due to impaired local circulation and infection or healing becomes impossible due to the gangrene. Recently, wound treatment models based on the use of topical insulin have been the subject of some studies. In this study, we aimed to evaluate the efficacy of topical NPH insulin use on wound healing for the treatment of full-thickness open wounds in diabetic and non-diabetic mice. A total of 72, non-diabetic and diabetic adult male Swiss Albino mice were used in the study. A full-thickness skin excision with a diameter of 1 cm was practiced on the back of all mice. Animals in diabetic and nondiabetic groups were divided into two sub-groups as NPH insulin used and control group. After the wound surface areas were digitally measured, the animals were sacrificed for histopathological and immunohistochemical examinations. Wound measurements revealed a significant reduction in the non-diabetic insulin treatment group at 7th and 14th days and at 3rd, 7th and 14th days of treatment in the diabetic insulin treatment group. Histopathological examinations showed that there was a significant increase in granulomatous inflammation in the wound site in the non-diabetic insulin treatment group at 3rd days and in the diabetic insulin treatment group at 14thdays. Immunohistochemical analyses showed that there was an increase in α-SMA at 3rd days and a decrease in TGF-β1 at 14th days in the diabetic insulin treatment group, while there was a significant decrease in IGF-I at 7th days in all diabetic groups. Topical NPH insulin application significantly accelerated healing in the treatment of diabetic and non-diabetic wounds with tissue loss in mice

Safety profile of second-line agents as add-on to oral monotherapy or dual therapy in uncomplicated type 2 diabetes in South Indian population

Background: Nowadays, there is an abundance of many therapeutic options available for the management of type 2 diabetes mellitus (DM). Hence, shifting the trend toward personalized treatment that focuses on the differences among different classes of pharmacological agents with regard to the mechanism of action, efficacy, and most important - the safety. Most of the clinical guidelines reconcile the risk-benefit ratio of the individual therapies. Moreover, there is limited evidence comparing the efficacy and safety of second-line drugs in combination therapies. It becomes crucial to rationalize the combination therapies with respect to attainment of glycemic targets, reduction in the short- and long-term complications and providing a better quality of life. In clinical practice, optimal treatment of type 2 DM must take into account the various comorbidities and adverse drug reactions (ADRs). Aims and Objective: The aims of the study were to assess the ADRs associated with second-line antidiabetic drugs when used as add-on agent in uncomplicated type 2 DM. Materials and Methods: Patients aged ≥18 years of age, diagnosed as uncomplicated type 2 DM who were previously receiving at least one oral antidiabetic drug (metformin or sulfonylurea) or dual-combination therapy (metformin+sulfonylurea) and for the first-time initiated on a second-line add-on agent, i.e., pioglitazone or dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin/vildagliptin) or α-glucosidase inhibitor (voglibose) or insulin (pre-mixed insulin [30% regular/70% NPH]) were included in the study. The ADRs associated with second-line agents were assessed based on hypoglycemic events, weight changes, frequency of ADRs, liver and renal function tests, and medical events reported. Results: A total of 240 patients (mean age 56.79 ± 11.73 years) were prescribed one of four different class of hypoglycemic agents. Overall, the median weight gain of 1.5 kg was observed in the insulin group, with no change of median weight in DPP-4 inhibitor group; while pioglitazone and voglibose group demonstrated a median weight loss of 1 and 0.5 kg, respectively, at the end of 6 months. The maximum number of hypoglycemic episodes was reported in insulin treatment group, i.e., 33; while least with DPP-4 inhibitor, i.e., 12. Out of 274 ADRs, the most common were gastrointestinal adverse effects, i.e., 30.66% and least were the dermatological ADRs (5.11%). Conclusion: Henceforth, DPP-4 inhibitor add-on group was found to be safest in terms of least hypoglycemic episodes and side effects when used as add-on therapy.

PROTECTIVE EFFECT OF INSULIN TREATMENT ON EARLY RENAL CHANGES IN STREPTOZOTOCIN-INDUCED DIABETIC RATS.

Chronic kidney disease is a progressive complication of diabetes mellitus (DM). This study aimed to analyse early renal changes in streptozotocin induced diabetic rats and demonstrate the effect of early treatment with insulin on kidney's histology. 30 male-adult Sprague-Dawley rats were included in the study. Diabetes was induced in 24 of the rats by a single injection of 65 mg/kg streptozotocin dissolved in saline. 5 units/day NPH insulin injection was started to 10 rats as treatment group and 11 rats were followed untreated. 6 rats constituted the control group. Induction of diabetes failed in 3 animals and 3 untreated rats died during the study. After 21 days, all rats were sacrificed and their kidneys were removed to obtain histological sections to be evaluated by light microscopy. Ten treated and 8 untreated diabetic rats and 6 healthy controls, totally 24 rats completed the study. There was a significant weight loss in treated and untreated diabetic groups and a weight gain in the control group (p<0.05). Final blood glucose levels were significantly higher in untreated diabetic group when compared to treated diabetic and control groups and higher in treated diabetic group when compared to control group. Histological analysis of kidney sections showed normal morphology in control group. Changes like increased mesangium, tubular atrophy and tubules with dilated lumen and irregular cell shapes were found in the untreated group whereas, glomerulus and mesangium showed similar morphology with control group with a few changes in tubules, in insulin-treated group. In DM, renal changes start at an early point and it is possible to prevent/delay those changes at this point with early intervention of insulin treatment.

Anti-Diabetic Effects of Amygdalus Lycioides Spach in Streptozocin-Induced Diabetic Rats.

Diabetes mellitus is a group of metabolic disorders characterized by elevated blood sugar and abnormalities in insulin secretion and action. There are many anti-diabetic plants, which might supply useful sources for developing new medicines that can be used in treatment of diabetes mellitus. The primary objective of the present investigation is to evaluate the anti-diabetic properties of the aerial parts of Amygdalus lycioides in streptozocin-induced diabetic rats. Sixty rats were divided into 6 groups: streptozocin-induced diabetic control, insulin-treated diabetic group, and four Amygdalus lycioides-treated diabetic groups (125, 250, 500, and 1000 mg/kg/day). After 2 weeks of plant extract administration, the effects of extracts on blood glucose, body weight, BUN, creatinine, total cholesterol, LDL, HDL, triglyceride, total protein, Na, K, and plasma enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) were analyzed. The pancreas of rats was also stained for stereological studies. Phytochemical evaluation of this extract showed the presence of flavonoids and tannins compounds. Glucose serum levels and glucose tolerance test showed a decrease in treatment with Amygdalus lycioides (1000 mg/kg). Serum total cholesterol, LDL, triglyceride, creatinine and alkaline phosphatase levels were decreased significantly by the extract but aspartate aminotransferase found to be increased after treatment. The total number and numerical density of beta cells increased in the Amygdalus lycioides group (1000 mg/kg). It seems that Amygdalus lycioides may act as a potential drug to treat diabetes and its complications. However, more investigations should be done to more clarify these results.

Intensified blood glucose treatment in diabetic patients undergoing a liver transplant: impact on graft evolution at 3months and at 5years.

The debate about the impact of intensified hyperglycemia treatment is still ranging. The main objective was to assess whether intensive glycemic control in hospitalized diabetic patients undergoing a liver transplant is associated with a lower rate of graft rejection at 3months and at 5years post-transplant. Cross-sectional study comparing a cohort of patients undergoing liver transplant in 2010 and 2011, in whom an intensive insulin protocol was applied, with a retrospective group of patients undergoing a liver transplant in 2005 and 2006, in whom a conventional insulin protocol was applied. Both diabetics and non-diabetics were compared. As intensive insulin therapy is applied mainly in diabetic patients, it is expected that, when comparing both periods, the treatment would only benefit those patients. The logistic regression model showed a statistically significant interaction between the treatment group and the presence of diabetes for the rejection rate 3months and 5years post-transplant. At both time points, the intensive insulin treatment group had lower rejection rates in the case of diabetic patients, which did not occur in non-diabetic patients. Our study shows a decrease in the rate of liver graft rejection in diabetic patients undergoing intensive insulin treatment.

Low-intensity pulsed ultrasound prevents muscle atrophy induced by type 1 diabetes in rats

BackgroundType 1 diabetes mellitus (T1DM) induces serious skeletal muscle atrophy. Low-intensity pulsed ultrasound (LIPUS) is a common treatment for skeletal muscle injury and is effective in accelerating the rate of muscle growth. However, to the best of our knowledge, whether LIPUS can improve skeletal muscle atrophy in type 1 diabetic rats has not been investigated.MethodsThe rats were randomly divided into four groups: the normal control group (NC); the sham-treated diabetic control group (DC); the diabetic, insulin-treated group (DI) as a positive control; and the diabetic LIPUS therapy group (DL). The DL rats were treated with LIPUS (1 MHz, 30 mW/cm2) on the gastrocnemius for 20 min/day.ResultsAfter 6 weeks, the rats in the DC group showed severe muscle atrophy. However, LIPUS significantly improved type 1 diabetes-induced muscle atrophy, as evidenced by significantly enhanced muscle cross-sectional area, muscle mass, and strength. Moreover, compared with the DC group, LIPUS significantly activated Akt and upregulated the expression of mTOR, and LIPUS downregulated the expression of MSTN, its receptor ActRIIB, and FoxO1.ConclusionsThese results indicate that LIPUS improved muscle atrophy induced by type 1 diabetes, and the MSTN/Akt/mTOR&FoxO1 signaling pathway may play a role in this improvement.

The effects of add-on exenatide to insulin on glycemic variability and hypoglycemia in patients with type 1 diabetes mellitus

To investigate the effect of add-on exenatide to insulin on glycemic excursion and the counter-regulatory hormone in response to hypoglycemia in patients with type 1 diabetes mellitus (T1DM). 30 patients with T1DM were recruited and randomly assigned to exenatide+insulin-treated group (group 1, n=15) or insulin-only-treated group (group 2, n=15) for 4weeks. All patients had continuous glucose monitor system (CGMS) applied at before (week-0) and after (week-4) treatment to evaluate the glycemic variability. All patients had an arginine-stimulated test at before and after treatment. Six patients from each group also had hypoglycemic clamp test to assess counter-regulatory hormone level. Patients in the exenatide group had significant reductions in body weight, body mass index (BMI), total insulin dose, bolus insulin dose, fructosamine, and glycemic excursion after 4weeks' treatment. Compared with patients in group 2, the mean amplitude of glycemic excursion (MAGE) and coefficient of variation (CV) of exenatide group decreased significantly. Similarly, a significant decrease of glucagon (GLC) in the arginine-stimulated test was found in group 1. No significant changes of GLC, growth hormone (GH), cortisol (COR), epinephrine (E), and norepinephrine (NE) were found in both groups during hypoglycemia clamp test. However, patients who had residual islet function in group 1 showed an upward trend of basic C-peptide (C-P) and GLC during the hypoglycemia period. Although exenatide could inhibit glucagon secretion during euglycemia or hyperglycemia in patients with T1DM, it has no effect on GLC and counter-regulatory hormones during hypoglycemia clamp in patients with no functional residual islet test.

111 - Insulin Treatment is Associated with Increased Cardiorenal Fibrosis Despite Maintaining Euglycemia in Experimental Diabetic Cardiomyopathy

Introduction: There is a high prevalence of diabetic cardiomyopathy among diabetics, characterized by diastolic dysfunction independent of coronary artery disease and hypertension, which is thought to be related to metabolic derangements and protein alterations. Diabetes mellitus (DM) is associated with cardiorenal fibrosis and heart failure, but the effects of insulin treatment on this pathophysiologic process is undefined. Our objective is to determine the cellular effects of insulin treatment on cardiorenal fibrosis in DM. Methods: Three groups of male Wistar rats (n = 9 to 15 per group): 1) Normal control; 2) Diabetic (DM) control; 3) Insulin-treated DM rats; were used. One dose of streptozotocin was administered to induce DM. Two months after induction of DM, Alzet pumps filled with insulin (11.5 u/kg/day) or saline as a sham control were serially implanted subcutaneously every 14 days over the course of 1 month. Cardiac structure and function was assessed by echocardiography. Neurohormones were measured by radioimmunoassay. Cardiac and renal tissue was collected upon animal sacrifice, and fibrosis was determined by picrosirius red and trichrome staining. Results: The development of diabetes was confirmed by glucose measurements: normal control 110 ± 3, DM control 435 ± 20, insulin-treated DM 108 ± 15 mg/dL (P < .01). There was a reduction in LV ejection fraction when normal control is compared to DM and insulin-treated DM groups (80.5 ± 1.6 versus 76.7 ± 1.7 and 77.4 ± 1.4%, P < .05). Echocardiography showed that LV diameter is greater for the DM and insulin-treated DM groups compared to normal controls (8.5 ± 0.3 and 8.0 ± 0.2 versus 6.2 ± 0.2 mm, P < .01). Histological analyses by picrosirius staining revealed that insulin-treated DM had an increase in LV interstitial fibrosis (3.6 ± 0.4 vs 1.8 ± 0.2 %, P < .01) and kidney cortex fibrosis (3.4 ± 0.3 vs 1.8 ± 0.2%, P < .01) versus DM group, both greater as compared to normal controls (P < .01). Furthermore, there was no difference in 24 hour urine protein excretion between insulin-treated DM and DM groups (P = .76), both increased as compare to normal controls (1.9 ± 0.2 vs 1.7 ± 0.2 vs 0.8 ± 0.1 mg/min, P < .01). Plasma cGMP was the lowest in the insulin-treated DM group vs DM vs normal controls (2.3 ± 0.2 vs 10.4 ± 1.3 vs 4.9 ± 0.9 pmol/ml, P < .05). Conclusion: The results demonstrated that despite the maintenance of euglycemia with insulin, there was an increase in cardiorenal fibrosis associated with attenuated plasma cGMP level in experimental model of DM. There is a need for glycemic agents that may have beneficial effects in cardiorenal fibrosis associated with diabetic cardiomyopathy.

Cerebroplacental ratio in pregnancies complicated by gestational diabetes mellitus.

To assess the relationship between the cerebroplacental ratio (CPR) and intrapartum and perinatal outcomes in pregnancies complicated by gestational diabetes mellitus (GDM). This was a retrospective cohort study of women with a non-anomalous singleton pregnancy diagnosed with GDM who delivered at Mater Mothers' Hospital between 2007 and 2015. CPR was measured in 1089 cases between 34 + 0 and 36 + 6 weeks' gestation. CPR values were compared between groups categorized according to GDM treatment (by diet, oral hypoglycemic agent (OHA) or insulin). The association between CPR and intrapartum and perinatal outcomes was evaluated. No difference in CPR was observed between treatment groups. Fetuses with CPR < 10th centile were significantly more likely to have adverse composite perinatal outcome (odds ratio (OR) = 2.93 (95% CI, 1.95-4.40)), preterm delivery and low birth weight than fetuses with CPR ≥ 10th centile (all P < 0.001). These associations were present regardless of the type of GDM treatment. Fetuses of women with insulin-controlled GDM had poorer neonatal outcomes than did fetuses of women treated with OHA or dietary control alone. The risk of adverse outcome was significantly increased in the insulin-treated group (OR = 1.75 (95% CI, 1.34-2.28); P < 0.001), which also had higher rates of preterm delivery and higher birth weight. Regardless of the type of treatment, a low CPR is associated with poorer neonatal outcome in women with GDM. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

BackgroundDiabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.ObjectiveTo evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.MethodsPancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).ResultsIslet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.ConclusionsDN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.