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Significance Self-administered insulin is the most important therapeutic to provide control over blood glucose levels for patients with type-1 diabetes. However, standard insulin therapy introduces a number of complications and subsequent issues with control of blood glucose levels. Here, we prepared a derivative of insulin with a molecular switch to provide glucose-mediated activation of the insulin molecule, toward the generation of more autonomous therapy with improved blood glucose control. This modified insulin, when administered in a diabetic mouse model, restores blood glucose levels following a glucose challenge (i.e., a simulated meal) faster than both standard insulin and a clinically used long-lasting insulin derivative. Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

Half of the global insulin supply for pharmaceutical application is produced using recombinant secretory expression by the yeast Saccharomyces cerevisiae.Molecular adaptation of insulin is necessary for secretory expression in S. cerevisiae.The effectiveness of insulin precursor expression by S. cerevisiae is determined by two main factors: dimerisation of insulin precursors and the thermodynamic folding stability of the insulin precursor.Insulin precursors can be adapted for highly efficient expression in S. cerevisiae by introducing removable structural elements that modify self-association properties and/or folding stability.Optimising large-scale production of insulin precursors, through structural adaptations for enhanced expression efficiency, is important to decrease CO2 emissions and conserve water and energy. Since the first administration of insulin to a person with diabetes in 1922, scientific contributions from academia and industry have improved insulin therapy and access. The pharmaceutical need for insulin is now more than 40 tons annually, half of which is produced by recombinant secretory expression in Saccharomyces cerevisiae. We discuss how, in this yeast species, adaptation of insulin precursors by removable structural elements is pivotal for efficient secretory expression. The technologies reviewed have been implemented at industrial scale and are seminal for the supply of human insulin and insulin analogues to people with diabetes now and in the future. Engineering of a target protein with removable structural elements may provide a general approach to yield optimisation. Since the first administration of insulin to a person with diabetes in 1922, scientific contributions from academia and industry have improved insulin therapy and access. The pharmaceutical need for insulin is now more than 40 tons annually, half of which is produced by recombinant secretory expression in Saccharomyces cerevisiae. We discuss how, in this yeast species, adaptation of insulin precursors by removable structural elements is pivotal for efficient secretory expression. The technologies reviewed have been implemented at industrial scale and are seminal for the supply of human insulin and insulin analogues to people with diabetes now and in the future. Engineering of a target protein with removable structural elements may provide a general approach to yield optimisation.

ObjectiveThis review aims to summarize the current management of type 2 diabetes principles, including oral hypoglycemic agents, types of insulin administration, diet maintenance, and various molecular approaches.MethodsA literature search was conducted in different databases such as Scopus, ScienceDirect, Google Scholar, and Web of Science by using the following keywords: type-2 diabetes mellitus (T2DM), first-line and second-line treatment, oral hypoglycemic agents, insulin administration, diet/nutritional therapy, gene and stem cell therapy, and diabetic complications.ResultsThe first-line treatment of T2DM includes administering oral hypoglycemic agents (OHAs) and second-line treatment by insulin therapy and some OHAs like Sulfonylurea’s (SU). The oral hypoglycemic or oral antidiabetic drugs have the function of lowering glucose in the blood. Insulin therapy is recommended for people with A1C levels > 7.0, and insulin administration is evolved drastically from the syringe, pump, pen, inhalation, insulin jet, and patch. The use of OHAs and insulin therapy during glycemic control has a severe effect on weight gain and other side effects. Hence, diet maintenance (macro and micronutrients) and nutritional therapy guidelines were also reviewed/recommended for safe T2DM management. Besides, the recent progress in molecular approaches that focuses on identifying new targets for T2DM (i.e.) consisting of gene therapy, stem cell therapy, and the modulation of insulin signaling pathways for the regulation of glucose storage and uptake also discussed.ConclusionThe analysis of all these key factors is necessary to develop a potential agent to cure T2DM and suggest that a combination of therapies will pave the way for advanced management of T2DM.

Background/Objectives: Hypoglycemic effect of camel milk supplementation in experimental rat model and significant reduction in doses of insulin in type 1 diabetic patients have been observed in our previous studies. This long-term study was undertaken to assess the efficacy, safety and acceptability of camel milk as an adjunct to insulin therapy in type 1 diabetics. Subjects/Methods: In this 2-year randomized clinical, parallel design study, 24 type 1 diabetics were enrolled and divided into two groups. Group I ( n =12) received usual care, that is, diet, exercise and insulin and Group II ( n =12) received 500 ml camel milk in addition to the usual care. Insulin requirement was titrated weekly by blood glucose estimation. Results were analyzed by using the regression technique. Results: In camel milk group, there was decrease in mean blood glucose (118.58±19–93.16±17.06 mg/dl), hemoglobin A1c levels (7.81±1.39–5.44±0.81%) and insulin doses (32.50±9.99–17.50±12.09 U/day, P <0.05). Out of 12 subjects receiving camel milk, insulin requirement in 3 subjects reduced to zero. There was nonsignificant change in plasma insulin and anti-insulin antibodies in both the groups. Conclusion: It may be stated that camel milk is safe and efficacious in improving long-term glycemic control, with a significant reduction in the doses of insulin in type 1 diabetic patients.

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin. Significance Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show that in mice with type 1 diabetes treated with insulin, the transient high blood glucose levels require production of glucagon, a hormone that will cause the liver to produce more glucose. Blocking the action of glucagon with an antibody to the glucagon receptor completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy. Suppressing glucagon action in combination with low-dose insulin would be a superior treatment for type 1 diabetes.

Background: Gestational diabetes mellitus (GDM) is a pregnancy complication characterized by second trimester hyperglycemia. Untreated, GDM is related to an increased risk for adverse pregnancy outcomes. Both beta cell dysfunction and insulin resistance underlie impaired glucose tolerance. Understanding the dominant mechanism predisposing to GDM may be important to provide effective treatment in order to improve perinatal outcomes. We hypothesize that insulin resistance rather that beta cell dysfunction predisposes to GDM. Methods: A 75g oral glucose tolerance test (OGTT) was performed on 2112 second-trimester pregnant women to determine the relationship between insulin resistance (HOMA-IR), beta cell function (HOMA-β), and the prevalence of abnormal glucose handling. Results: High insulin resistance raised the risk of GDM (relative risk (RR) 6.1, 95% confidence interval (CI) (4.4–8.5)), as did beta cell dysfunction (RR 3.8, 95% CI (2.7–5.4)). High insulin resistance, but not beta cell function, enhances the necessity for additional glucose lowering medication on top of a low carbohydrate diet in women diagnosed with GDM. Conclusions: Both high insulin resistance and beta cell dysfunction increase the risk of GDM. As increased insulin resistance, rather than beta cell function, is related to an insufficient response to a low carbohydrate diet, we speculate that insulin sensitizers rather than insulin therapy may be the most targeted therapeutic modality in diet-insensitive GDM.

Gestational diabetes mellitus (GDM) is defined as “glucose intolerance that is first diagnosed during pregnancy”. Mothers with GDM and their infants may experience both short and long term complications. Dietary intervention is the first therapeutic strategy. If good glycaemic control is not achieved, insulin therapy is recommended. There is no consensus on which nutritional approach should be used in GDM. In the last few years, there has been growing evidence of the benefits of a low glycaemic index (LGI) diet on diabetes and cardiovascular disease. The effect of a LGI diet on GDM incidence has been investigated as well. Several studies observed a lower incidence of GDM in LGI diet arms, without adverse maternal and fetal outcomes. The main positive effect of the LGI diet was the reduction of 2-h post-prandial glucose (PPG). Several studies have also evaluated the effect of the LGI diet in GDM treatment. Overall, the LGI diet might have beneficial effects on certain outcomes, such as 2-h PPG, fasting plasma glucose and lipid profile in patients with GDM. Indeed, most studies observed a significant reduction in insulin requirement. Overall, according to current evidence, the LGI nutritional approach is safe and it might therefore be considered in clinical care for GDM.

Abstract Background For the treatment of diabetes mellitus (DM) in dogs, novel insulins with decreased injection frequency while maintaining safety and efficacy are desirable. Insulin fused with immunoglobulin-fragment-crystallizable (Fc) has an ultra-long plasma half-life because it recycles through cells, protected from proteolysis. Hypothesis Glycemic control can be achieved in diabetic dogs with a recombinant fusion protein of a synthetic insulin and canine Fc (AKS-218d) administered subcutaneously once-weekly. Animals Five client-owned dogs with naturally occurring DM. Methods Prospective clinical trial in dogs with DM that were recruited from the UC Davis Veterinary Teaching Hospital and local veterinary clinics. Dogs previously controlled using intermediate-acting insulin q12h were transitioned to once-weekly injections of a preliminary construct identified as AKS-218d. The dose of AKS-218d was titrated weekly for 8 weeks based on clinical response and continuous interstitial glucose monitoring. Clinical signs, body weight, serum fructosamine concentrations, and mean interstitial glucose concentrations (IG) over the preceding week were compared between baseline (before AKS-218d) and during the last week of treatment. Data were compared using nonparametric paired tests. Results Once-weekly AKS-218d, compared to baseline twice-daily insulin therapy, resulted in no significant changes in clinical signs, median (range) body weight (+0.4 kg [−0.5-1.1]; P = .6), fructosamine concentration (−75 mmol/L [−215 to +126]; P = .4), or mean IG (+81 mg/dL [−282 to +144]; P = .8). No adverse reactions were reported. Conclusion Control of clinical signs, body weight, and maintenance of glycemia was achieved with this once-weekly novel insulin construct in 4 of 5 dogs.

Diabetes mellitus is an endocrine disease in which the pancreas does not produce sufficient insulin or the body cannot effectively use the insulin it produces. Insulin therapy has been the best choice for the clinical management of diabetes mellitus. The current insulin therapy is via subcutaneous injection, which often fails to mimic the glucose homeostasis that occurs in normal individuals. This provokes numerous attempts to develop a safe and effective noninvasive route for insulin delivery. Oral delivery is the most convenient administration route. However, insulin cannot be well absorbed orally because of its rapid enzymatic degradation in the gastrointestinal tract. Therefore, nanoparticulate carriers such as polymeric nanoparticles and micelles are employed for the oral delivery of insulin. These nanocarriers protect insulin from degradation and facilitate insulin uptake via a transcellular and/or paracellular pathway. This review article focuses on the application of nanoparticles and micelles in insulin oral delivery. The recent advances in this topic are also reviewed.