Diabetic Loss Research Articles

Albuminuria and Rapid Kidney Function Decline as Selection Criteria for Kidney Clinical Trials in Type 1 Diabetes Mellitus.

The optimal criteria to select individuals with type 1 diabetes mellitus (T1D) and albuminuric or normoalbuminuric diabetic kidney disease (DKD), who are at risk of rapid kidney function decline, for clinical trials are unclear. This study analyzed data from the Preventing Early Renal Loss in Diabetes (PERL) clinical trial, which investigated whether allopurinol slowed kidney function decline in persons with T1D and early-to-moderate DKD. Rates of iohexol GFR (iGFR) and estimated GFR (eGFR) decline during the three-year study were compared by linear mixed effect regression between participants enrolled based on a history of moderately or severely increased albuminuria (N=394) and those enrolled based on a recent history of rapid kidney function decline (≥3 ml/min/1.73 m2/year) in the absence of a history of albuminuria (N=124). The association between baseline albuminuria and iGFR/eGFR decline during the trial was also evaluated. Rates of eGFR decline during the trial were higher in participants with a history of albuminuria than in those with a history of rapid kidney function decline (-3.56 [95% confidence intervals {CI} -3.17, -3.95] versus -2.35 [95% CI: -1.86, -2.84] ml/min/1.73 m2/year, p=0.001). Results were similar for iGFR decline, although the difference was not significant (p=0.07). Within the history of albuminuria group, the rate of eGFR decline was -5.30 (95% CI -4.52, -6.08) ml/min/1.73m2/year in participants with severely increased albuminuria as compared to -2.97 (95% CI 2.44, -3.50) and -2.32 (95% CI -1.61, -3.03) ml/min/1.73m2/year in those with moderately increased or normal/mildly increased albuminuria at baseline (p<0.001). Severely increased albuminuria at screening is a powerful criterion for selecting persons with T1D at high risk of kidney function decline. A history of rapid eGFR decline without a history of albuminuria is less effective for this purpose but it can still identify individuals with T1D who will lose kidney function more rapidly than expected from physiological aging. ClinicalTrials.gov, NCT02017171.

RIPK1 is dispensable for cell death regulation in β-cells during hyperglycemia

ObjectiveReceptor-interacting protein kinase 1 (RIPK1) orchestrates the decision between cell survival and cell death in response to tumor necrosis factor (TNF) and other cytokines. Whereas the scaffolding function of RIPK1 is crucial to prevent TNF-induced apoptosis and necroptosis, its kinase activity is required for necroptosis and partially for apoptosis. Although TNF is a proinflammatory cytokine associated with β-cell loss in diabetes, the mechanism by which TNF induces β-cell demise remains unclear. MethodsHere, we dissected the contribution of RIPK1 scaffold versus kinase functions to β-cell death regulation using mice lacking RIPK1 specifically in β-cells (Ripk1β-KO mice) or expressing a kinase-dead version of RIPK1 (Ripk1D138N mice), respectively. These mice were challenged with streptozotocin, a model of autoimmune diabetes. Moreover, Ripk1β-KO mice were further challenged with a high-fat diet to induce hyperglycemia. For mechanistic studies, pancreatic islets were subjected to various killing and sensitising agents. ResultsInhibition of RIPK1 kinase activity (Ripk1D138N mice) did not affect the onset and progression of hyperglycemia in a type 1 diabetes model. Moreover, the absence of RIPK1 expression in β-cells did not affect normoglycemia under basal conditions or hyperglycemia under diabetic challenges. Ex vivo, primary pancreatic islets are not sensitised to TNF-induced apoptosis and necroptosis in the absence of RIPK1. Intriguingly, we found that pancreatic islets display high levels of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and low levels of apoptosis (Caspase-8) and necroptosis (RIPK3) components. Cycloheximide treatment, which led to a reduction in cFLIP levels, rendered primary islets sensitive to TNF-induced cell death which was fully blocked by caspase inhibition. ConclusionsUnlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.

A metabolic redox relay supports ER proinsulin export in pancreatic islet β cells.

ER stress and proinsulin misfolding are heralded as contributing factors to β cell dysfunction in type 2 diabetes, yet how ER function becomes compromised is not well understood. Recent data identify altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple β cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that β cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas thioredoxin-interacting protein suppression restored ER redox and proinsulin trafficking. Taken together, we propose that β cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.

SAT117 Diabetes And Vision: Can Chatgpt Educate Our Diabetic Patients?

Abstract Disclosure: G. Wu: None. E. Cheng: None. W. Zhao: None. A. Wong: None. N. Mansubi: None. P. Dorado: None. H. Gim: None. Background: Diabetic retinopathy is the leading cause of blindness in working-age Americans. Nearly 4.1 million U.S. adults are affected by retinopathy, but over 50% of the patients do not receive an eye examination and diagnosis before vision loss. ChatGPT is a new Artificial Intelligence (AI) trained model launched on 11/30/2022 that generates real-time comprehensive responses. Purpose: Can ChatGPT educate our patients about Diabetic retinopathy? Methods: A retina specialist created a scoring system of Keywords per question to assess ChatGPT responses, maximum score of 6 points per question: 1) I am diabetic and I have a hemoglobin/A1C of 6.5. I still cannot read my book. Why? Keywords: eye MD/optometrist, kidney complications, neuropathy, macular edema/diabetic retinopathy, stroke, healthcare team 2) I am diabetic and my fasting blood sugar is 200 but I suddenly lost vision in one eye. Why? Keywords: eye MD/optometrist, retinal detachment, retinal vein/artery occlusion, vitreous hemorrhage, stroke, healthcare team 3) I am a new diabetic and when I look in the mirror I am missing one part of my face. Why? Keywords: eye MD/optometrist, retinal detachment, kidney complications, neuropathy, diabetic retinopathy/macular edema, stroke, healthcare team 4) My hemoglobin/A1C is 8 and my striped dress looks wavy. Why? Keywords: eye MD/optometrist, diabetic retinopathy, macular edema, metamorphopsia, stroke, healthcare team 5) I have high cholesterol, my pants became too tight, and my blood sugar is borderline at 120-150 but now I cannot see to read. Why? Keywords: eye MD/optometrist, diabetic retinopathy, metabolic syndrome, macular edema, vitreous hemorrhage, healthcare team. Results: Keyword Scores: Qn 1 = 2/6 (diabetic retinopathy, health care team); Qn 2 = 3/6 (retinal detachment, vein occlusion, health care team); Qn 3 =1/6 (healthcare team); Qn 4 = 2/6 (diabetic retinopathy, health care team); Qn 5 = 2/6 (diabetic retinopathy, health care team). For all of the answers: None mention macular edema which is an important part of visual loss in diabetes. Qn 4 describes metamorphopsia (wavy dress) which is pathognomonic for macular edema and it is missing from the answer. High blood sugar=3/5 diabetic retinopathy=4/5; blindness/loss of vision=3/5; Stroke, eye MD/optometrist, American Academy of Ophthalmology, nephropathy/kidney, macular edema, foot/nerve neuropathy, ADA/Endocrine Society, or ACC/AHA=0/5. Conclusions: ChatGPT is the newest Artificial Intelligence mediated chatbot. It provides basic responses to questions about the eye in readable text and it is a good starting point for future AI chatbots. Presentation: Saturday, June 17, 2023

Weight Loss in Diabetes: Pharmacological Management and Other Strategies

Diabetes and obesity are prevalent metabolic disorders that present a significant global public health challenge. This review article provides a comprehensive overview of pharmacological and surgical management strategies for weight loss in diabetes. Diabetes, characterized by high blood glucose levels, and obesity, resulting from excessive body fat accumulation, are closely linked, making effective management essential. Pharmacological interventions for weight loss in diabetes include metformin, which can lead to modest weight reduction in some patients. GLP-1 receptor agonists, such as Semaglutide, liraglutide, and exenatide, offer effective glycemic control and weight loss options. Dual GIP/GLP-1 agonists, particularly Tirzepatide, show promise in treating diabetes and obesity with significant weight loss and glycemic control observed in clinical trials. SGLT-2 inhibitors, like dapagliflozin and empagliflozin, not only manage diabetes but also offer cardiovascular benefits and weight reduction. Amylin mimetics, exemplified by pramlintide, regulate post-meal glucose levels, suppress glucagon secretion, and promote satiety, leading to sustained weight reduction in diabetic patients. Gastric bypass surgery, an option for select individuals with obesity and diabetes, shows significant weight loss and improved metabolic profiles. By understanding these treatment options, healthcare professionals can develop personalized management plans combining lifestyle modifications, pharmacotherapy, and surgery where appropriate. Such approaches can lead to better patient outcomes, including weight loss and improved metabolic control. Ongoing research is essential to explore the long-term efficacy and safety of these interventions to optimize diabetes and obesity management in diverse patient populations.

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

Previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among persons with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N=469) and with type 2 diabetes (T2D) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (N=7,973). Baseline CAN was ascertained using ECG-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss ≥-5 ml/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed effect, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 (95%CI [-1.93, -0.37], P= 4.0x10-3) ml/min/1.73m2/year in PERL and 0.34 (95%CI [-0.49, -0.19], P= 6.3x10-6) ml/min/1.73m2/year in ACCORD. This translated in 2.11 (95% CI [1.23-3.63], P=6.9x10-3) and 1.39 (95% CI [1.20-1.61], P=1.1x10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (HR=2.60, 95%CI [1.15-5.45], p=0.02 in PERL and HR=1.54, 95%CI [1.28-1.84], P=3.8×10-6 in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help develop new therapies to prevent kidney function decline in patients with diabetes.

Combined Treatment of Persistent Diabetic Macular Edema with Aflibercept and Triamcinolone Acetonide in Pseudophakic Eyes.

Background and Objectives: The main cause of the vision loss in diabetics is the development of diabetic macular edema, regardless of the stage of diabetic retinopathy. The paper aimed to examine whether the additional intravitreal application of triamcinolone acetonide to continuous anti-vascular endothelial growth factor therapy could improve therapeutic outcomes for pseudophakic eyes with persistent diabetic macular edema. Materials and Methods: twenty-four pseudophakic eyes with refractory diabetic macular edema, that had appeared despite three previously administered intravitreal injections of aflibercept, were divided into two groups (twelve eyes in each group). The first group continued to have aflibercept administered according to a fixed dosing regimen (once in two months). Triamcinolone acetonide 10 mg/0.1 mL (administered once per four months) was included for the second group, i.e., their treatment continued with a combination of aflibercept + triamcinolone acetonide. Results: The reduction in central macular thickness was higher in the eyes treated with combined therapy (aflibercept + triamcinolone acetonide) compared with the use of aflibercept alone during the entire 12-month follow-up period (3rd month p = 0.019; 6th month p = 0.023; 9th month p = 0.027; 12th month p = 0.031). As was evident from the p-values, the differences were statistically significant. No statistically significant difference was recorded for visual acuity: 3rd month p = 0.423; 6th month p = 0.392; 9th month p = 0.413; 12th month p = 0.418. Conclusions: Combined anti-vascular endothelial growth factor and steroid therapy leads to a better anatomical outcome of persistent diabetic macular edema in pseudophakic eyes, but does not lead to a more significant improvement in visual acuity than continuous anti-VEGF therapy alone.

Weight loss in diabetics of 2 unbalanced revealing neoplasia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Knockdown of SIRT3 perturbs protective effects of irisin against bone loss in diabetes and periodontitis.

A well-recognized risk factor for periodontitis, diabetes mellitus (DM) aggravates periodontal disease with increasing alveolar bone loss. As a novel myokine, irisin is closely linked with bone metabolism. Nonetheless, the effects of irisin on periodontitis under diabetic conditions and the underlying mechanisms remain poorly understood. Here, we showed that local irisin treatment ameliorates alveolar bone loss and oxidative stress, increases SIRT3 expression within periodontal tissues of our experimentally-induced diabetes and periodontitis (DP) rat models. By culturing the periodontal ligament cells (PDLCs) in vitro, we found that irisin could partially rescue inhibited cell viability, mitigate accumulated intracellular oxidative stress, ameliorate mitochondrial dysfunctions, and restore disturbed osteogenic and osteoclastogenic capacities of PDLCs when exposed to high glucose and pro-inflammatory stimulation. Furthermore, lentivirus-mediated SIRT3 knockdown was employed to unravel the underlying mechanism by which SIRT3 mediated irisin's beneficial effects on PDLCs. Meanwhile, in SIRT3-deficient mice, irisin treatment did not protect against alveolar bone destruction and oxidative stress accumulation in DP models, which underlined the crucial role of SIRT3 in mediating the positive effects of irisin on DP. Our findings, for the first time, revealed that irisin attenuates alveolar bone loss and oxidative stress via activation of the SIRT3 signaling cascade, and highlighted its therapeutic potential for the treatment of DP.

Kcnma1 is involved in mitochondrial homeostasis in diabetes-related skeletal muscle atrophy.

Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca2+ - and voltage-gated K+ channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.

Islet amyloid polypeptide does not suppress pancreatic cancer

ObjectivesPancreatic cancer risk is elevated approximately two-fold in type 1 and type 2 diabetes. Islet amyloid polypeptide (IAPP) is an abundant beta-cell peptide hormone that declines with diabetes progression. IAPP has been reported to act as a tumour-suppressor in p53-deficient cancers capable of regressing tumour volumes. Given the decline of IAPP during diabetes development, we investigated the actions of IAPP in pancreatic ductal adenocarcinoma (PDAC; the most common form of pancreatic cancer) to determine if IAPP loss in diabetes may increase the risk of pancreatic cancer. MethodsPANC-1, MIA PaCa-2, and H1299 cells were treated with rodent IAPP, and the IAPP analogs pramlintide and davalintide, and assayed for changes in proliferation, death, and glycolysis. An IAPP-deficient mouse model of PDAC (Iapp−/−; Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER) was generated for survival analysis. ResultsIAPP did not impact glycolysis in MIA PaCa-2 cells, and did not impact cell death, proliferation, or glycolysis in PANC-1 cells or in H1299 cells, which were previously reported as IAPP-sensitive. Iapp deletion in Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER mice had no effect on survival time to lethal tumour burden. ConclusionsIn contrast to previous reports, we find that IAPP does not function as a tumour suppressor. This suggests that loss of IAPP signalling likely does not increase the risk of pancreatic cancer in individuals with diabetes.

JS-HR-11: HOT TOPICS IN URIC ACID RESEARCH

The mechanism between hyperuricemia, arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease is becoming clearer (Figure cited from the article ‘Update on Hypertension Research in 2021’, Hypertension Research. 2022;45(8):1276 to 1297). However, it remains unclear whether treatment of hyperuricemia improves these diseases. In this session, we will introduce some recent topics of uric acid research. The PERL (Preventing Early Renal Loss in Diabetes) trial and the CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) showed that urate-lowering treatment with allopurinol, one of xanthine oxidase (XO) inhibitors, did not slow the decline in eGFR as compared with placebo. These results were similar with the results of FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) from Japan. Furthermore, the PRIZE (Program of Vascular Evaluation Under Uric Acid Control by the Xanthine Oxidase Inhibitor Febuxostat: Multicenter, Randomized, Controlled) study showed that febuxostat did not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia. These results suggest that treatment of hyperuricemia could not directly prevent chronic kidney disease (CKD) and/or arteriosclerosis. In contrast, there are many studies that showed the positive relationship between uric acid and hypertension. Lowering serum uric acid levels could reduce blood pressure, but it is unclear that lowering serum uric aclid levels might be directly causing the results in preventing CKD progression, arteriosclerosis, and cardiovascular events. These results suggest that we should carefully choose the treatable patients with hyperuricemia and hypertension.

Tympanometry Comparison of Diabetic Type I and Diabetic Type II Rats

Hearing impairment affects over two-thirds of adults with diabetes. We investigated whether rat models of type 1 and type 11 diabetes display impaired auditory function. Tympanometry measurements were conducted in Sprague-Dawley rats (control, n = 20), streptozotocin-induced type I diabetic Sprague-Dawley rats (n = 20) at 42 - 56 days old; Zucker rats (Hos: ZFDM-Lean (fa/+, n = 20) and Zucker Type 2 Diabetic rats (ZFDM (Hos: ZFDM-fa/fa); n = 20)), 90 days old. All rats were male. Control animals had normal type A tympanograms. Tweny one (75%) of the tympanic membranes in the diabetic type I group produced abnormal tympanograms: 46% were type B, 28% had no peak found, and 1% were type C. The ear canal measurements were lower in the left ear in type I mice (0.19 ± 0.07) and higher in the left ear for type II mice (0.23 ± 0.15 ml) compared to the controls of 0.39 ± 0.14 ml) and (0.2 ± 0.12 ml) respectively (P < 0.0001). The compliances for the right ear and left ear were lower for the type II diabetic group (0.18 ± 0.05 ml) and (0.18 ± 0.05 ml) compared to the control group (0.28 ± 0.19 ml) and (0.28 ± 0.49 ml) (P < 0.0001) respectively. In conclusion, control rats exhibited type A tympanograms with a highly functional middle ear system. Diabetic type I rats (n = 20) mostly exhibited type B tympanograms with a less compliant middle ear system. Compliance was reduced in the diabetic type I and II animals compared to the control. Future studies should utilise histological methods alongside tympanometry. Sections of the middle ear could be used to analyze ossicle size and confirm size differences. This information would be useful in avenues for treatment options for hearing loss in diabetes.

Hidden blood loss of minimally invasive hybrid lumbar interbody fusion: an analysis of influencing factors

BackgroundLumbar interbody fusion(LIF) is the leading way to treat Lumbar Degenerative Diseases(LDD). At present, there is a lack of research on the influencing factors of hidden blood loss in minimally invasive hybrid lumbar interbody fusion. This study comprehensively explores the definite factors affecting the hidden blood loss in minimally invasive hybrid lumbar interbody fusion.Materials and methodsOne hundred patients with Lumbar degenerative diseases who underwent minimally invasive hybrid lumbar interbody fusion in our center were included. Demographics, laboratory data, surgical data, and radiographic data were collected. The Gross equation and Sehat equation were used to calculate the estimated value of hidden blood loss. Multi-factor linear regression analysis was used to determine the influencing factors of hidden blood loss.ResultWe reviewed and collected 100 patients who underwent minimally invasive hybrid approach, mean age 65 ± 10 years, male: female 37:63; 17 patients of diabetes and 83 patients of non-diabetes; Total blood loss was 645.59 ± 376.37 ml, hidden blood loss was 421.39 ± 337.45 ml, the hidden blood loss percentage was 57 ± 26%. Results from the multi-factorial linear regression model: Diabetes (p < 0.05), hypertension (p < 0.05), psoas thickness (p < 0.05) and dorsal extensor group thickness (p < 0.05) were potential risk factors for postoperative hidden blood loss.ConclusionAlthough minimally invasive hybrid approach is minimally invasive surgery, there is still a significant amount of hidden blood loss. There is a greater risk of blood loss in diabetes, hypertension and preoperative MRI assessment of thickness of the psoas, thickness of the dorsal extensor group.

Continuous glucose monitoring reveals a novel association between duration and severity of hypoglycemia, and small nerve fiber injury in patients with diabetes.

Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes. A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days. CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0-37.5) vs 38.6 (29.2-46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9-37.5) vs 37.5 (29.2-46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8-41.7) vs 35.4 (28.1-44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = -0.342, P = 0.031). Duration in level 1 (181-250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05). Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Nobiletin ameliorates glucose tolerance by protecting against β-cell loss in type-2 diabetic db/db mice

BackgroundNobiletin, a polymethoxy flavone contained in the peel of Citrus reticulata, has been known to have health benefits especially those related to improvement of type 2 diabetes. Our previous in vitro study demonstrated the insulinotropic and anti-apoptotic effects of nobiletin in pancreatic β-cells. These effects of nobiletin are postulated to be responsible for its anti-diabetic activity. PurposeWe evaluated the anti-diabetic effects of nobiletin on pancreatic β-cells of type 2 diabetic db/db mice. MethodsNobiletin was filled into an osmotic pump and implanted subcutaneously in the back of db/db mice for 2 weeks with continuous administration. The mice were then used for the experiments to elucidate the in vivo effects of nobiletin on glucose intolerance. ResultsThe continuous subcutaneous administration of nobiletin using osmotic pumps significantly reduced blood glucose levels in non-fasting state and during an oral glucose tolerance test. The nobiletin administration also ameliorated insulin sensitivity determined by insulin tolerance test, which was likely due to a reduction of white adipose tissue weight. In addition, β-cell mass was significantly larger in nobiletin-administered db/db mice compared to vehicle-administered db/db mice. These results suggest that continuous administration of nobiletin ameliorates glucose tolerance in type 2 diabetes, which is mediated by improving not only insulin resistance but also insulin secretion, the latter being due to protection against β-cell loss in diabetes. ConclusionNobiletin would have a valuable effect on the prevention of type 2 diabetes.

Exercise mitigates calpain induced Purkinje cell loss in diabetes

Calpain-1 is a ubiquitous calcium dependent cysteine protease and found in cytoplasm as well as mitochondria. We have earlier reported that active calpain-1 is translocated from cytosol to mitochondria and activates MMP9. Calpain-1 activation is detrimental to the heart in several different ways, but there is little evidence that it can degrade Purkinje cell protein (PCP-4) and impair contractility in diabetes. Our hypothesis is that in diabetes, PCP-4 is degraded by calpain-1, causing contractile dysfunction that can be mitigated by exercise. To test this hypothesis, we recruited four groups of mice, 1) db/+ control, 2) db/+ with exercise, 3) db/db, 4) db/db with exercise. The mice were exercised on treadmill for 8 weeks as per American Veterinary Research Guidelines. Adding calcium to isolated cardiomyocytes caused them to lose shape and die. Compared with live myocytes, we observed high calpain-1 levels as well as significantly lower levels of PCP-4 and increased levels of calmodulin and calmodulin kinase II (CaMKII) in dead myocytes. We used the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) plasmid to knock down calpain-1 in HL-1 myocytes which restored the levels of PCP-4 along with calmodulin and CaMKII. In vivo, we found upregulated levels of calpain-1 in db/db mice (diabetic) as compared to db/+ which were mitigated in the exercised mice. Conclusively our data strongly suggests that in diabetes there is high induction of calpain-1 with degrades PCP-4, a protein important for contractility and exercise can mitigate this.

Diabetic Proteinuria Revisited: Updated Physiologic Perspectives.

Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin–angiotensin axis or of sodium–glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.

Long-term trends in incidence and prevalence of severe sight impairment due to diabetes in South East Scotland before and after implementation of diabetic retinopathy screening

The study set out to examine the impact of the introduction of a national diabetic retinopathy screening programme in Scotland in 2006 on incidence and trends in severe sight impairment (SSI) certification due to diabetes over three decades. We analysed SSI certification due to diabetic eye disease in Fife, Scotland, between 2010 and 2019 and compared it to previously published estimates from 1990 onwards. Population estimates of the general population and those with diabetes were obtained from the National Records of Scotland and the National Diabetes Register, NHS SCI Diabetes, respectively. Mean annual incidence of SSI in the population with diabetes, 1990–2019, before and after the introduction of diabetic retinopathy screening was compared using a Mann–Whitney U Test. Mean incidence in 2007–2019 was 19.8/100,000 and was significantly less than the period before the systematic screening, 1990–2006 (57.5/100,000, p &lt; .001). Mean SSI incidence due to diabetes in Fife between 2010 and 2019 was significantly lower than in the previous decades ( p &lt; .001) at 16.4 per 100,000 for the population with diabetes, per year ( SD 10.0; 95% confidence interval: [9.2, 23.5]) compared to 42.7 per 100,000 in 2000–2009 and 64.3 per 100,000 in 1990–1999. This study demonstrates a significant reduction in the annual incidence of SSI due to diabetes before and after the introduction of the screening programme provides evidence for the benefit of systematic diabetic retinopathy screening programmes. Other factors including improved management of diabetes and risk factors will have also had an impact emphasizing the importance of a multidisciplinary approach to the prevention of sight loss in diabetes.

Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review.

The approval of once daily liraglutide, 3.0 mg, and once weekly semaglutide, 2.4 mg, for chronic weight management provides a novel effective strategy against obesity. The reliable models that might predict weight reducing potential at the individual level have not been identified yet. However, the coexistence of diabetes has been consistently related with less effective response than in people without this comorbidity. We aimed to review the efficacy of GLP-1 RAs approved for weight management in individuals with and without diabetes and discuss some potential mechanisms for consistently observed differences in efficacy between these two populations. The mean weight loss difference between GLP-1 RAs and placebo as add-on to lifestyle intervention in patients with diabetes was 4% to 6.2% compared to 6.1 to 17.4% in people without diabetes. Semaglutide compared to liraglutide resulted in greater weight loss. Some hypothetical explanations for the weaker anti-obesity response for both GLP-1 RAs in people with diabetes include the background medications that promote weight gain, the fear of hypoglycaemia inherently related to the treatment of diabetes, a decrease in glycosuria and subsequently less weight loss in diabetics, an altered microbiota in patients with obesity and diabetes and a genetic background that predispose to weight gain in patients with diabetes. Moreover, people with diabetes may have had obesity for longer and may be less adherent to exercise, which seems to potentiate the effects of GLP-1 RA. Emerging multimodal approaches combining peptides targeting receptors at different levels might therefore be of additional benefit particularly in patients with diabetes.