The frequency and timing of bedside BG monitoring can be individualized; however, monitoring is typically performed before meals and at bedtime in people who are eating; every 4 to 6 hours in people who are NPO nothing by mouth or receiving continuous enteral feeding; and every 1 to 2 hours for people on continuous intravenous insulin or those who are critically ill.

Some bedside BG monitoring is indicated in individuals without known diabetes but receiving treatments known to be associated with hyperglycemia e. glucocorticoids, octreotide, parenteral nutrition and enteral nutrition The implementation and maintenance of quality control programs by health-care institutions helps to ensure the accuracy of bedside BG monitoring 19, The use of glucose meters with bar coding capability has been shown to reduce data entry errors in medical records Data management programs that transfer bedside BG monitoring results into electronic records allow evaluation of hospital-wide glycemic control Capillary blood glucose CBG point of care testing POCT should be interpreted with caution in the critically ill patient population.

Poor perfusion indices may yield conflicting capillary, arterial and whole BG values using POCT glucose meters 23— Venous or arterial samples are preferred when using a POCT meter for this patient population. Clinical decision support system software integrating CBG POCT can aid in trend analysis, medication dosing, reduce prescription error and reduce length of stay Electronic glucose metric data and web-based reporting systems may pose utility for monitoring glycemic management performance within an organization and enhance opportunities for external benchmarking A number of studies have demonstrated that inpatient hyperglycemia is associated with increased morbidity and mortality in noncritically ill hospitalized people 1,28, Current recommendations are based mostly on retrospective studies, clinical experience and judgement.

Glycemic targets for hospitalized people with diabetes are modestly higher than those routinely advised for outpatients with diabetes given that the hospital setting presents unique challenges for the management of hyperglycemia, such as variations in patient nutritional status and the presence of acute illness.

For the majority of noncritically ill hospitalized people, recommended preprandial BG targets are 5. Lower targets may be considered in clinically stable hospitalized people with a prior history of successful tight glycemic control in the outpatient setting, while higher targets may be acceptable in terminally ill people or in those with severe comorbidities.

a missed meal 18, Acute hyperglycemia in the intensive care setting is not unusual and results from a number of factors, including stress-induced counter-regulatory hormone secretion and the effects of medications administered in the ICU Glycemic targets for people with pre-existing diabetes who are in the critical care setting have not been firmly established.

Early trials showed that achieving normoglycemia 4. However, subsequent trials in mixed populations of critically ill patients did not show a benefit of targeting BG levels of 4. A meta-analysis of trials of intensive insulin therapy in the ICU setting suggested benefit of intensive insulin therapy in surgical patients, but not in medical patients Conversely, the Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation NICE-SUGAR study, the largest trial to date of intensive glucose control in critically ill medical and surgical patients, found an increase in day all-cause mortality hazard ratio [HR] 1.

Furthermore, intensive insulin therapy has been associated with an increased risk of hypoglycemia in the ICU setting The use of insulin infusion protocols with proven efficacy and safety minimizes the risk of hypoglycemia 35— There are few occasions when intravenous insulin is required, as most people with type 1 or type 2 diabetes admitted to general medical wards can be treated with subcutaneous insulin.

Intravenous insulin, however, may be appropriate for people who are critically ill with appropriate BG targets , people who are not eating and in those with hyperglycemia and metabolic decompensation e.

diabetic ketoacidosis [DKA] and hyperosmolar hyperglycemic state [HHS] see Hyperglycemic Emergencies in Adults chapter, p. The evidence to date suggests there is no benefit to intravenous insulin over subcutaneous insulin post-acute stroke 3, Health-care staff education is a critical component of the implementation of an intravenous insulin infusion protocol.

Intravenous insulin protocols should take into account the patient's current and previous BG levels as well as the rate of change in BG , and the patient's usual insulin dose.

Several published insulin infusion protocols appear to be both safe and effective, with low rates of hypoglycemia; however, most of these protocols have only been validated in the ICU setting, where the nurse-to-patient ratio is higher than on medical and surgical wards 3, BG determinations can be performed every 1 to 2 hours until BG has stabilized.

With the exception of the treatment of hyperglycemic emergencies e. DKA and HHS , consideration should be given to concurrently providing people receiving intravenous insulin with some form of glucose e.

intravenous glucose or through parenteral or enteral feeding. Hospitalized people with type 1 and type 2 diabetes may be transitioned to scheduled subcutaneous insulin therapy from intravenous insulin.

Short- or rapid- or fast-acting insulin can be administered 1 to 2 hours before discontinuation of the intravenous insulin to maintain effective blood levels of insulin.

If intermediate- or long-acting insulin is used, it can be given 2 to 3 hours prior to intravenous insulin discontinuation. People without a history of diabetes, who have hyperglycemia requiring more than 2 units of intravenous insulin per hour, likely require insulin therapy and can be considered for transition to scheduled subcutaneous insulin therapy.

The initial dose and distribution of subcutaneous insulin at the time of transition can be determined by extrapolating the intravenous insulin requirement over the preceding 6- to 8-hour period to a hour period. Dividing the total daily dose as a combination of basal and bolus insulin has been demonstrated to be safe and efficacious in medically ill patients 40, The management of individuals with diabetes at the time of surgery poses a number of challenges.

Acute hyperglycemia is common secondary to the physiological stress associated with surgery. Pre-existing diabetes-related complications and comorbidities may also influence clinical outcomes. Acute hyperglycemia has been shown to adversely affect immune function 42 and wound healing 43 in animal models.

Observational studies have shown that hyperglycemia increases the risk of postoperative infections 44,45 , renal allograft rejection 46 , and is associated with increased health-care resource utilization In people undergoing coronary artery bypass grafting CABG , a pre-existing diagnosis of diabetes has been identified as a risk factor for postoperative sternal wound infections, delirium, renal dysfunction, respiratory insufficiency and prolonged hospital stays 48— Intraoperative hyperglycemia during cardiopulmonary bypass has been associated with increased morbidity and mortality rates in individuals with and without diabetes 51— A systematic review of randomized controlled trials supports the use of intravenous insulin infusion targeting a blood glucose of 5.

This was demonstrated by a marked reduction in surgical site infections odds ratio 0. The perioperative glycemic targets for minor or moderate surgeries are less clear. Older studies comparing different methods of achieving glycemic control during minor and moderate surgeries did not demonstrate any adverse effects of maintaining perioperative BG levels between 5.

Attention has been placed on the relationship between postoperative hyperglycemia and surgical site infections. While the association was well documented, the impact and risks of intensive management was less clear.

The risk of hypoglycemia was increased but there was no increased risk of stroke or death. The included studies looked at the intraoperative and immediate postoperative period and used intravenous insulin to achieve intensive targets.

The included studies were mostly cardiac and gastrointestinal and were found to have a moderate risk of bias Rapid institution of perioperative glucose control must be carefully considered in patients with poorly controlled type 2 diabetes undergoing monocular phacoemulsification cataract surgery with moderate to severe nonproliferative diabetic retinopathy because of the possible increased risk of postoperative progression of retinopathy and maculopathy The outcome of vitrectomy, however, does not appear to be influenced by perioperative control Given the data supporting tighter perioperative glycemic control during major surgeries and the compelling data showing the adverse effects of hyperglycemia, it is reasonable to target glycemic levels between 5.

The best way to achieve these targets in the postoperative patient is with a basal bolus insulin regimen 61, This approach has been shown to reduce postoperative complications, including wound infections. Despite this knowledge, surgical patients are often treated with correction supplemental rapid-acting insulin alone 63 which may not adequately control BG.

The benefits of improved perioperative glycemic control must be weighed against the risk of perioperative hypoglycemia. Anesthetic agents and postoperative analgesia may alter the patient's level of consciousness and awareness of hypoglycemia.

The risk of hypoglycemia can be reduced by frequent BG monitoring and carefully designed management protocols. In general, insulin is the preferred treatment for hyperglycemia in hospitalized people with diabetes People with type 1 diabetes must be maintained on insulin therapy at all times to prevent DKA.

Scheduled subcutaneous insulin administration that consists of basal, bolus prandial and correction supplemental insulin components is the preferred method for achieving and maintaining glucose control in noncritically ill hospitalized people with diabetes or stress hyperglycemia who are eating 35, Bolus insulin can be withheld or reduced in people who are not eating regularly; however, basal insulin should not be withheld.

Stable people can usually be maintained on their home insulin regimen with adjustments made to accommodate for differences in meals and activity levels, the effects of illness and the effects of other medications.

In the hospital setting, rapid-acting insulin analogues are the preferred subcutaneous bolus and correction insulins Insulin programs that only react to, or correct for, hyperglycemia have been demonstrated to be associated with higher rates of hyperglycemia 61,66— Insulin is often required temporarily in hospital, even in people with type 2 diabetes not previously treated with insulin.

In these insulin-naive people, there is evidence demonstrating the superiority of basal-bolus-correction insulin regimens 61, A number of protocols have been published as part of studies 61,66,69— These studies have typically started insulin-naive people on 0.

breakfast, lunch and dinner ; correction doses of the bolus insulin are provided if BG values are above target.

Daily review of the person's BG measurements and modification of insulin doses, as required, facilitates the achievement of target blood glucose measurements. When comparing effective protocols, the following was observed. One study compared basal-bolus plus correction insulin with glargine and glulisine vs.

Average BG levels were not different, but rates of hypoglycemia were. Another study 74 found no difference in BG levels or rates of hypoglycemia when comparing insulin glargine vs.

detemir, when used as the basal insulin in a basal-bolus program. Yet another study 71 found that using a weight-based algorithm to titrate insulin glargine resulted in obtaining target BG levels faster than a glucose-based algorithm, with no difference in the rates of hypoglycemia.

More recently, a study compared a basal-bolus plus correction insulin regimen with a program that was basal plus correction The basal-bolus group had slightly lower BG through the day, which was not statistically significant, with no difference in FBG or in rates of hypoglycemia.

Taken together with the earlier studies from this group 61,66 , it would appear that successful management of in-hospital diabetes requires early and aggressive administration of basal insulin combined with bolus insulin, typically in the form of rapid-acting insulin analogue, similar to the approach used in the outpatient setting.

To date, no large studies have investigated the use of non-insulin antihyperglycemic agents on outcomes in hospitalized people with diabetes.

Stable hospitalized people with diabetes without these contraindications can often have their home antihyperglycemic medications continued while in the hospital.

However, if contraindications develop or if glycemic control is inadequate, these drugs should be discontinued and consideration given to starting the patient on a basal-bolus-supplemental insulin regimen. The advantages and disadvantages of various noninsulin antihyperglycemic therapies in hospital are discussed in detail in a recent review article A recent randomized but unblinded study compared sitagliptin plus basal and correctional insulin with a more traditional basal-bolus-correctional insulin program in hospitalized people with diabetes The glycemic outcomes were similar between the 2 groups; however, the basal-bolus-correctional group had a higher mean glucose than similarly insulin-treated subjects in other studies 61, This less-aggressive treatment may explain the lack of difference between the sitagliptin and the bolus insulin groups.

Medical nutrition therapy including nutritional assessment and individualized meal planning is an essential component of inpatient glycemic management programs. A consistent carbohydrate meal planning system may facilitate glycemic control in hospitalized people and facilitate matching prandial insulin doses to the amount of carbohydrate consumed 61,66,75,78— In hospitalized people with diabetes receiving parenteral nutrition, insulin can be administered in the following ways: as scheduled regular insulin dosing added directly to the parenteral solution; or as scheduled intermediate- or long-acting subcutaneous insulin doses A separate intravenous infusion of regular insulin may be an alternative method to achieve glycemic control in critical care For scheduled subcutaneous insulin dosing or regular insulin added directly to parenteral solutions, the selected starting insulin dose may be based on the current estimated TDD of insulin, the composition of the parenteral nutrition solution and the patient's weight Considering the patient's individual clinical situation is important when determining insulin dosing.

Subcutaneous correction supplemental insulin may be used in addition to scheduled insulin dosing and dose adjustments made to scheduled insulin should be adjusted based on the BG pattern.

For hospitalized people with diabetes on enteral feeding regimens, there are few prospective studies examining insulin management. In 1 randomized controlled trial, low-dose basal glargine insulin with regular insulin correction dosing was compared against regular insulin correction supplemental insulin dosing with the addition of NPH in the presence of persistent hyperglycemia and demonstrated similar efficacy for glycemic control The type of feed solution and duration of feed cyclical vs.

continuous should be considered. People with diabetes receiving bolus enteral feeds may be treated in the same manner as people who are eating meals. Correction supplemental insulin can be administered, as needed; added to the same bolus insulin.

An insulin with a shorter half-life, such as NPH, may be preferred for intermediate duration feeding schedules i. overnight , while regular or rapid-acting insulin may be more appropriate to manage hyperglycemia induced by bolus feeding schedules.

In the event that the parenteral or enteral nutrition is unexpectedly interrupted, intravenous dextrose may be required to prevent hypoglycemia depending on the last dose and type of insulin administered.

When parenteral or enteral feeding schedules are adjusted in terms of carbohydrate content or duration, the insulin type and dose will need to be re-assessed. Although the optimal management of hyperglycemia in people receiving high-dose oral corticosteroids has not been clearly defined, glycemic monitoring for 48 hours after initiation of steroids may be considered for people with or without a history of diabetes 35, For management of hyperglycemia, treatment with a basal-bolus with correction insulin regimen was more effective and safer than a correction supplemental insulin-only regimen 85 , although addition of NPH dosed variably from once a day at time of glucocorticoid administration to every 6 hours depending on glucocorticoid used was not demonstrated to improve glycemic outcomes 86, Although data for self-management in the hospitalized setting is limited, self-management in hospital may be appropriate for people who are mentally competent and desire more autonomy over their diabetes.

The majority of evidence pertains to continuous subcutaneous insulin infusion CSII therapy, where continuation of patient-managed insulin delivery has been associated with reduced episodes of severe hyperglycemia and hypoglycemia 88 and high levels of patient satisfaction In general, any person requiring insulin therapy who is self-managing diabetes in the hospital setting should be able to physically self-administer insulin and perform self-monitoring of blood glucose SMBG independently, be familiar with the recommended insulin routine, understand sick-day management guidelines and utilize a flowsheet to facilitate communication of BG results and insulin dosing between the patient and health-care providers.

The person with diabetes and the health-care provider, in consultation with nursing staff, must agree that patient self-management is an appropriate strategy while hospitalized. Hospitals should have policies and procedures for the assessment of suitability for self-management.

Although the data are limited, it appears that CSII can be safely continued in the hospital setting under certain circumstances People maintained on CSII may have decreased length of stay 90 ; however, this may reflect the severity of illness rather than a glycemic control advantage.

People maintained on CSII may have less hypoglycemia than those managed by the admitting clinician. People on CSII are encouraged to continue this form of therapy whenever safe and feasible in hospital.

Successful published inpatient protocols include assessment of pump specific self-management skills i. how to adjust their basal rate, administer a bolus dose, insert an infusion set, fill a reservoir, suspend the pump and correct a CBG result outside their target range , pre-printed orders, flow sheets and patient consents 88,91, If appropriate supports are not available, CSII may be discontinued and a basal-bolus-subcutaneous insulin regimen or intravenous insulin infusion may be initiated.

An increasing number of people are being maintained on CSII during short elective surgical procedures without any reported adverse events 93 , necessitating close collaboration between anesthesia and diabetes management teams. Different pump manufacturers will recommend discontinuing pumps for certain hospital-based procedures e.

radiology, cautery, external beam radiation. To promote a collaborative relationship between the hospital staff and the patient, and to ensure patient safety, hospitals must have clear policies and procedures in place to guide the use of CSII in the inpatient setting Documents that stipulate contraindications for continued CSII, procedures to guide medical management of CSII and a consent form outlining the inpatient terms of use 92 support the safe use of CSII use in hospital.

Specific algorithms and order sets for management of CSII peri-operatively and during labour and delivery have been published 93, Institution-wide programs to improve glycemic control in the inpatient setting include the formation of a multidisciplinary steering committee, professional development programs focused on inpatient diabetes management 95,96 , policies to assess and monitor the quality of glycemic management, interprofessional team-based care including comprehensive patient education and discharge planning as well as standardized order sets, protocols and algorithms for diabetes care within the institution.

Implementation of such a program can result in improvements in in-hospital glycemic control 97, Computerized and mobile decision support systems that provide suggestions for insulin dosing have also been used and have been associated with lower mean BG levels 26,— ; hypoglycemia can be an unintended consequence of tighter glycemic control 70, The timely consultation of glycemic management teams has also been found to improve the quality of care provided, reduce the length of hospital stay and lower costs , , although differences in glycemic control were minimal Deployment of nurses , , nurse practitioners and physician assistants with specialty training has been associated with greater use of basal-bolus insulin therapy and lower mean BG levels.

A provincial survey of over 2, people with diabetes admitted to hospital found that people were more likely to be satisfied with their diabetes care in hospital if they had confidence that the team was knowledgeable about diabetes, presented a consistent message and acknowledged them in their diabetes care Programs that include self-management education, such as assessment of barriers and goal setting, have also been associated with improvements in glycemic control 97, Institutional implementation of hospital glycemic management programs require metrics to monitor progress, assess safety, length of stay and identify opportunities for improvement Implementation of inpatient hyperglycemia quality improvement programs evaluated with real-time metrics have been shown to improve glycemic control and safety of insulin ordering 97, To date, metrics for monitoring glycemic control programs in hospitals have not been established This lack of standardization limits the ability for benchmarking and comparison of different quality-improvement programs and protocols.

Further study into the development and implementation of appropriate standardized metrics for hospital glycemic management programs is warranted. Interventions that ensure continuity of care, such as arranging continuation of care after discharge 97 , telephone follow up and communication with primary providers at discharge , have been associated with a post-discharge reduction in A1C Providing people with diabetes and their family or caregivers with written and oral instructions regarding their diabetes management at the time of hospital discharge will facilitate transition to community care.

Comprehensive instructions may include recommendations for timing and frequency of home glucose monitoring; identification and management of hypoglycemia; a reconciled medication list, including insulin and other antihyperglycemic medications; and identification and contact information for health-care providers responsible for ongoing diabetes care and adjustment of glucose-lowering medications.

Communication of the need for potential adjustments in insulin therapy that may accompany adjustments of other medications prescribed at the time of discharge, such as corticosteroids or octreotide, to people with diabetes and their primary care providers is important.

Hypoglycemia remains a major barrier to achieving optimal glycemic control in hospitalized people with diabetes. Standardized treatment protocols that address mild, moderate and severe hypoglycemia may help mitigate this risk.

Education of healthcare workers about factors that increase the risk of hypoglycemia, such as sudden reduction in oral intake, discontinuation of parenteral or enteral nutrition, unexpected transfer from the nursing unit after rapid-acting insulin administration or a reduction in corticosteroid dose 78 are important steps to reduce the risk of hypoglycemia.

Insulin is considered a high-alert medication and can be associated with risk of harm and severe adverse events. BG, blood glucose; CBG , capillary blood glucose; CABG , coronary artery bypass grafting; CSII , continuous subcutaneous insulin infusion; ICU , intensive care unit; NPH , neutral protamine Hagedorn; POC , point of care; TDD , total daily dose.

Chapter Glycemic Management in Adults With Type 1 Diabetes. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults. Treatment of Diabetes in People With Heart Failure. Literature Review Flow Diagram for Chapter In-Hospital Management of Diabetes. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.

PLoS Med 6 6 : e pmed For more information, visit www. Halperin reports personal fees from Dexcom, Novo Nordisk, and QHR technologies, outside the submitted work. Miller reports personal fees from Eli Lilly, Novo Nordisk, Sanofi, and AstraZeneca; and grants and personal fees from Boehringer Ingelheim, Janssen, Merck, outside the submitted work.

Sarah Moore reports personal fees from Diabetes Care Alliance Boehringer Ingelheim Eli Lilly Alliance , and Merck Canada, outside the submitted work. No other authors have anything to disclose. All content on guidelines. ca, CPG Apps and in our online store remains exactly the same.

For questions, contact communications diabetes. Become a Member Order Resources Home About Contact DONATE. Next Previous. Key Messages Recommendations Figures Full Text References.

Chapter Headings Introduction Screening for and Diagnosis of Diabetes and Hyperglycemia in the Hospital Setting Glucose Monitoring in the Hospital Setting Glycemic Control in the Non-Critically Ill Patient Glycemic Control in the Critically Ill Patient Role of Intravenous Insulin Role of Subcutaneous Insulin Role of Noninsulin Antihyperglycemic Agents Role of Medical Nutrition Therapy Special Clinical Situations Organization of Care Safety Other Relevant Guidelines Author Disclosures.

Key Messages Hyperglycemia is common in hospitalized people, even among those without a previous history of diabetes, and is associated with increased in-hospital complications, longer length of stay and mortality. Insulin is the most appropriate pharmacologic agent for effectively controlling glycemia in hospital.

A proactive approach to glycemic management using scheduled basal, bolus and correction supplemental insulin is the preferred method. The use of correction-only supplemental insulin, which treats hyperglycemia only after it has occurred, should be discouraged as the sole modality for treating elevated blood glucose levels.

For the majority of noncritically ill hospitalized people with diabetes, preprandial blood glucose targets should be 5. For critically ill hospitalized people with diabetes, blood glucose levels should be maintained between 6. Hypoglycemia is a major barrier to achieving targeted glycemic control in the hospital setting.

Health-care institutions should develop protocols for the assessment and treatment of hypoglycemia. Key Messages for People with Diabetes If your admission to hospital is planned, talk with your health-care providers e.

surgeon, anesthetist, primary care provider, diabetes health provider, etc. before you are admitted in order to develop an in-hospital diabetes care plan that addresses such issues as: Who will manage your diabetes in the hospital? Will you be able to self-manage your diabetes?

What adjustments to your diabetes medications or insulin doses may be necessary before and after medical procedures or surgery? Individuals with type 2 diabetes are frequently low in magnesium and when provided with magnesium supplementation, their insulin resistance significantly improves Tip: incorporate tasty sources of magnesium into your diet, such as dark leafy greens, spinach , nuts, seeds, avocado, dark chocolate, tofu and fatty fish like halibut.

Oral supplementation, Epsom salt baths and magnesium oils are all ways that you can increase your magnesium levels. The research on the benefits just keeps on increasing!

Some benefits include reduced perceived stress, reduced anxiety, reduced depressive symptoms, better quality of life, decreased sleep disturbance, improved cognition Long term meditation practise is associated with improved brain health, offsetting typical age-related decline.

And, it importantly improves insulin resistance and glucose intolerance — as well as reducing blood pressure, oxidative stress and inflammation Curcumin, the major part of turmeric, has multiple effects, some of which include: reducing blood glucose levels, stimulating insulin secretion and improving the function of the cells that secrete insulin Exercise is undoubtedly one of the best ways to improve glucose uptake into our cells.

Exercise can induce transporters in our cells that help draw glucose into the muscle tissue, clearing it from the blood. Here are some science-backed exercise tips for insulin sensitivity. Our team of Nutritionist and Functional Medicine Practitioners are on hand to support you with with goals.

Whether you have insulin resistance, pre-diabetes or diagnosed type 2 diabetes, our team specialises in helping clients reverse all the above through natural therapies.

For more information on how we help those with or at risk of type 2 diabetes, CLICK HERE. Meet the team behind Steve Grant Health and understand their areas of speciality and how they can help you achieve your goals.

We Specialise in Optimising Cardiometabolic Health, Digestive Health, and Human Performance using Nutrition, Lifestyle, and Functional Medicine.

Learn about our process from enquiry to consultations as well as the support packages that we offer. Get in touch today and book a free discovery call with one of our clinicians to learn more about how we can support your goals.

Get in touch today. I first went to Steve Grant Health in July after feeling super low energy, sleeping badly and struggling to motivate myself to train for months. The final straw was missing a period which scared me into finding out what the problem was.

After an initial consultation Steve sent me for After an initial consultation Steve sent me for a series of blood tests, and as soon as the results were back I saw him a second time to talk through the results, and get a plan of action put into place. I was advised to switch up my nutrition and to follow a supplement protocol for 8 weeks which worked like a dream.

I felt like a new person, my periods came back and have been regular ever since and I now sleep through the night most nights. I have also been able to get back to training, which as a personal trainer, is really important to me and my business. I had my bloods re- tested in November to confirm that everything had improved since my original testing.

I have been labelled as a type 2 diabetic or pre diabetic for nearly 15 years. After a stressful period in my life and losing my way somewhat with my diet and lifestyle, my average blood sugars HbA1C had increased from a previous 7. Following a consultation with Steve, where he reviewed my previous lab test and ran 2 additional lab tests, reviewed my nutrition and current lifestyle and began to formulate a plan.

Steve offered weekly support and food diary reviews, and to my amazement doubled, if not tripled the amount of food I was eating.

We also used a blood glucometer to test how my bloods were reacting to certain meals, allowing me to manage my blood sugars and understand the effects certain foods were having on them. After 3 months it was time for my diabetic review and the follow up blood tests.

I knew things were going well because I had been tracking my blood sugar levels gradually dropping over the past 3 months, along with my body weight which was now 11kg lighter. The good thing is I know it is not over now, Steve has set me some new goals for when I go for another review in 6 months.

I still have to continue with my healthy eating habits, but the best thing is I want to continue. The past three months have completely change how I approach my nutrition and lifestyle, and in such a short time I feel so much better and my self-confidence is now returning. I then had the good sense to ask him to He is able to provide the most personal and bespoke care wherever I travel.

I have referred several colleagues as well as my own daughter. I will certainly to continue this as I am in awe of his knowledge, ability and manner. Steve has truly been a life changer for me and I am forever grateful. I thoroughly enjoy my sessions with Steve.

He is attentive and responsive, always listening carefully and always knowledgeable about nutrition, as well as the wider world of human therapy. He develops simple and effective programs that are strict and focussed without being intimidating.

His instructions are clear and simple and His instructions are clear and simple and delivered when promised. By being flexible, supportive and encouraging he has empowered me not just to stick to my nutrition plan but to really enjoy it.

All in all, I am very happy with the results. As well as pretty much achieving my initial goals, I have also been pleasantly surprised to experience unexpected improvements.

Perhaps more importantly, Steve has helped me to change the way that I think and feel about food and drink. I no longer crave the things I know are bad for me.

I can still enjoy them occasionally but, against a background of generally healthy living, I actually enjoy them much more. I came to Steve in April having been referred by my rheumatologist. I had severe fibromyalgia and chronic fatigue which was preventing me from working and socializing. I was house-bound and in a lot of pain around the chest, neck and shoulders.

At the time I had dropped weight At the time I had dropped weight to 7st From the beginning Steve was so encouraging and understanding. Reducing calorie intake can help lower insulin levels in people living with excess weight or obesity who have type 2 diabetes or metabolic syndrome.

Diets high in added sugar are associated with insulin resistance and may promote the development of metabolic disease In a small study from , otherwise healthy people were tasked with eating an increased amount of either candy sugar or peanuts fat. In another small study from , otherwise healthy adults consumed jams containing varying amounts of sugar.

The adults who consumed high sugar jams saw their insulin levels rise significantly as compared with those who ate the lower-sugar jams Fructose is a type of natural sugar found in table sugar, honey, fruit, corn syrup, agave, and syrup.

Indeed, one study found that replacing glucose or sucrose with fructose actually lowered peak post-meal blood sugar and insulin levels, especially in people with prediabetes or type 1 or type 2 diabetes A high intake of sugar in any form has been shown to increase insulin levels and promote insulin resistance if consumed for a length of time.

Aerobic exercise appears to be very effective at increasing insulin sensitivity in people living with obesity or type 2 diabetes 27 , 28 , One study looked at the effect of sustained aerobic exercise versus high intensity interval training on metabolic fitness in men with obesity Although both groups experienced improvements in fitness, only the group that performed sustained aerobic activity experienced significantly lower insulin levels And lastly, combining aerobic and resistance exercise may be the best choice when it comes to positively affecting insulin sensitivity and levels 32 , Aerobic exercise, strength training, or a combination of both may help lower insulin levels and increase insulin sensitivity.

Cinnamon is a delicious spice loaded with health-promoting antioxidants. Recent studies suggest that both individuals living with insulin resistance and those with relatively normal insulin levels who supplement with cinnamon may experience enhanced insulin sensitivity and decreased insulin levels 34 , 35 , In one small, well-designed study, women with PCOS who took 1.

In another small, well-designed study, individuals living with type 2 diabetes who took mg of cinnamon powder twice daily for 3 months had lower fasting insulin and insulin resistance than those who took a placebo Improvements in insulin and insulin sensitivity were most pronounced for individuals with higher BMIs Some studies have found that adding cinnamon to foods or beverages lowers insulin levels and increases insulin sensitivity, but results are mixed.

Refined carbs include simple sugars as well as grains that have had the fibrous parts removed. Some examples are cereal with added sugar, highly processed fast foods, foods made with refined flour like certain breads and pastries, and white rice Regularly consuming refined carbs can lead to several health problems, including high insulin levels and weight gain 40 , Furthermore, refined carbs have a high glycemic index GI.

Some studies comparing foods with different glycemic loads have found that eating a high-glycemic-load food raises insulin levels more than eating the same portion of a low-glycemic-load food, even if the carb contents of the two foods are similar 43 , However, other studies comparing high-glycemic-load and high-glycemic-index diets with low-glycemic-load and low-glycemic-index diets have found no difference in their effects on insulin levels or insulin sensitivity 45 , Replacing refined carbs, which are digested quickly and can sharply raise blood sugar, with slower-digesting complex carbs and whole grains may help lower insulin levels.

Other studies have shown that getting up and walking around, rather than sitting for prolonged periods, can help keep insulin levels from spiking after a meal One study looked at the effect of physical activity on insulin levels in men with extra weight who were at risk for type 2 diabetes.

Those who took the most steps per day had the greatest reduction in insulin levels and belly fat compared with those who took the fewest steps Avoiding sitting for prolonged periods and increasing the amount of time you spend walking or doing other moderate activities may help reduce insulin levels.

Intermittent fasting an eating plan where you have set hours for eating and set hours for fasting during a hour period has been popping up in headlines recently, specifically around its possible weight loss benefits. Research also suggests intermittent fasting may help reduce insulin levels as effectively as or more effectively than daily calorie restriction 50 , A study compared alternate-day fasting with calorie restriction in adults with extra weight or obesity and insulin resistance Those using alternate-day fasting for 12 months had greater reductions in fasting insulin and insulin resistance than those who restricted their calorie intake, as well as those in the control group A doctor or nutritionist can help you figure out whether intermittent fasting is right for you and how to do it safely.

Intermittent fasting may help reduce insulin levels. However, more research needs to be done, and this way of eating may not suit everyone. Soluble fiber provides a number of health benefits, including aiding in weight loss and reducing blood sugar levels.

After you eat, the soluble fiber in food absorbs water and forms a gel, which slows down the movement of food through your digestive tract. This promotes feelings of fullness and keeps your blood sugar and insulin from rising too quickly after a meal 53 , One observational study from found that individuals assigned female at birth who ate the most soluble fiber were half as likely to be insulin-resistant as individuals assigned female who ate the least soluble fiber Soluble fiber also helps feed the friendly bacteria that live in your colon, which may improve gut health and reduce insulin resistance.

In a 6-week controlled study of older women with obesity, those who took flaxseed which contains soluble fiber experienced greater increases in insulin sensitivity and lower insulin levels than women who took a probiotic or placebo Overall, fiber from whole foods appears to be more effective at reducing insulin than fiber in supplement form, although results are mixed.

One study found that insulin decreased when people consumed black beans but not when they took a fiber supplement Soluble fiber, especially from whole foods, has been shown to increase insulin sensitivity and lower insulin levels, particularly in people living with obesity or type 2 diabetes.

The distribution of fat throughout your body is determined by age, sex hormones, and genetic variation An overabundance of belly fat — also known as visceral or abdominal fat — in particular is linked to many health issues. Visceral fat can promote inflammation and insulin resistance, which drives hyperinsulinemia 59 , 60 , A small study from suggests that losing visceral fat can lead to increased insulin sensitivity and lower insulin levels Interestingly, another small study from found that people who lost abdominal fat retained the benefits for insulin sensitivity even after regaining a portion of the belly fat There is no way to specifically target visceral fat when losing weight.

Frederick Sanger sequenced bovine insulin in , identifying its exact amino-acids composition, 2 , 3 and was awarded with the Nobel Prize for Chemistry in Insulin is a peptide hormone that is produced and released by islets pancreatic β cells, that finely regulates the glucose uptake from blood into liver, fat, and skeletal muscle cells.

Under normal physiological conditions, increased plasma glucose levels lead to increased insulin secretion and circulating insulin levels, thereby stimulating glucose transfer into peripheral tissues and inhibiting hepatic gluconeogenesis. A relatively safe and well accepted approach in the prevention and treatment of IR is via lifestyle interventions.

Nutritional intervention is an important first step that emphasizes a low-calorie and low-fat diet that stimulates excessive insulin demands.

In addition, increased physical activity is recommended to help increase energy expenditures and improve muscle insulin sensitivity, this two approach represent the fundamental treatment for IR.

In this review, the mechanism of insulin action and IR are first described to promote the development of new therapeutic strategies. Further, the direct and indirect effects of insulin on target tissues are discussed to better understand the pivotal role of tissue crosstalk in systemic insulin action.

Lastly, diseases associated with IR are discussed and summarized. Many methods and multiple surrogate markers have been developed to calculate the IR.

We then summarize the current measurements and potential biomarkers of IR to facilitate the clinical diagnosis. Finally, we provide the general approaches including lifestyle intervention, specific pharmacologic interventions and clinical trials to reduce IR.

Insulin is an endocrine peptide hormone with 51 amino acids and composed of an α and a β chain linked together as a dimer by two disulfide bridges 18 along with a third intrachain disulfide bridge in the α chain. Accumulation of reports have demonstrated that IR is a complex metabolic disorder with integrated pathophysiology.

The exact causes of IR has not been fully determined, 36 , 37 , 38 but ongoing research seeks to better understand how IR develops. Here, we focus on the underlying mechanism of IR including direct defective of insulin signaling, epidemiological factors, interorgan metabolic crosstalk, metabolic mediators, genetic mutation, epigenetic dysregulation, non-coding RNAs, and gut microbiota dysbiosis.

As has been mentioned, the proper modulators acting on different steps of the signaling pathway ensure appropriate biological responses to insulin in different tissues. Thus, the diverse defect in signal transduction contributes to IR. Insulin exerts its biological effects by binding to its cell-surface receptors, therby activating specific adapter proteins, such us the insulin receptor substrate IRS proteins principally IRS1 and IRS2 , Src-homology 2 SH2 and protein-tyrosine phosphatase 1B PTP1B , eventually promoting downstream insulin signaling involving glucose homeostasis.

Most individuals that are obese or diabetic exhibit decreased surface INSR content and INSR kinase IRK activity. Second, decreased expression or serine phosphorylation of IRS proteins 44 , 45 can reduce their binding to PI3K, thereby down-regulating PI3K activation and inducing apparent IR. It is generally accepted that diverse downstream targets of Akt activation lead to different distal signaling in target tissues response to insulin.

Different investigations have indicated that premenopausal women exhibit many less metabolic disorders than men, including lower incidence of IR, although this effect diminishes severely when women reach the postmenopausal situation.

Concomitantly, clinical and experimental observations 70 , 71 have revealed that endogenous estrogens can protect against IR primarily through ER-α activation in multiple tissues, including in the brain, liver, skeletal muscle, and adipose tissue, in addition to pancreatic β cells.

Further, female hormone estrogens are determinants that mediate body adiposity levels and body fat distribution in addition to glucose metabolism and insulin sensitivity. Specifically, insulin sensitivity and capacities for insulin responses in women is significantly higher than men. Male homozygous for the polymorphism of PPP1R3A gene that involved in glycogen synthase activity are significantly younger at diagnosis than female.

Thus, additional studies are required to understand mechanisms underlying sex differences and IR development. South Asian children exhibit greater IR compared with white European children, while girls are more insulin resistant than boys, with sex and ethnicity differences related to insulin sensitivity and body composition.

Despite the above objective factors, some modifiable lifestyle factors including diet, exercise, smoking, sleep and stress are also considered to contribute to IR.

Further, circadian clocks disruption might also be an important factor to IR development via various factors including clock gene mutations, disturbed sleep cycles, shift work and jet lag.

Different investigations suggest that vitamin D supplementation might reduce IR in some people due to increasing insulin receptor genes transcription and anti-inflammatory properties, 95 while some researchers found that Vitamin D has no effect on IR. Both experimental animals and clinical studies have shown that many hormones can induce IR including glucocorticoids GCs , 97 cortisol, 98 growth hormone, 99 and human placental lactogen, which may decrease the insulin-suppressive effects on glucose production and reduce the insulin-stimulated glucose uptake.

Several other clinical medications including anti-adrenergic such as salbutamol, salmeterol, and formoterol , HIV protease inhibitors, , atypical antipsychotics and some exogenous insulin that may improve IR because of the disordered insulin signaling.

All together, there may have synergistic effects of different risk factors on insulin resistance, scientific researchers should cooperate with medical experts to reduce the chances of becoming insulin resistant. As discribed above, insulin signaling calibrates glucose homeostasis by limiting hepatic glucose output via decreased gluconeogenesis and glycogenolysis activities.

These processes consequently increase the glucose uptake rates in muscle and adipose tissues. In addition, insulin profoundly affects lipid metabolism by increasing lipid synthesis in liver and fat cells Fig.

Despite stimulated glucose uptake, insulin rapidly reduces hepatic glucose output and hepatic glucose production HGP by activating glycogen synthesis, and suppressing glycogenolysis and gluconeogenesis in liver.

Insulin induces SREBP-1c maturation via a proteolytic mechanism started in the endoplasmic reticulum ER , wherein hepatic IR is highly associated with hepatic steatosis.

Accordingly, restoration of nuclear SREBP-1c expression in liver-specific Chrebp defective mice normalized expression of some lipogenic genes, while not affecting glycolytic genes expressing.

In contrast, ChREBP overexpression alone failed to promote the expression of lipogenic genes in the livers of mice lacking active SREBPs. Together, these data demonstrate that SREBP-1c mediates the induction of insulin lipogenic genes, but that SREBP-1c and ChREBP are both necessary for harmonious induction of glycolytic and lipogenic genes.

Altogether, these above pathways and components can be used to clarify the popular pathophysiology of hepatic IR. The lipid metabolisms including increased de novo lipogenesis and attenuation of lipolysis in the adipose tissue largely coordinate with glucose homeostasis response to insulin stimulation.

De novo lipogenesis regulation in adipose is similar to that in livers, wherein adipose-ChREBP is a major determinant of adipose tissue fatty acid production and systemic insulin sensitivity, that is induced by GLUT4-mediated glucose uptake, and genetically ablating ChREBP impairs insulin sensitivity in adipose tissue In addition, lipogenic gene FASN and DGAT mRNA expression in adipose tissue have been shown to correlate strongly and positively with insulin sensitivity, which were may reduced by larger adipocytes in adipose tissue of obese individuals.

The lipogenesis stimulation of insulin is also reduced in larger, more insulin-resistant cells. Insulin suppression of lipolysis includes the hydrolytic cleavage of triglycerides, resulting in the generation of fatty acids and glycerol.

The best understood effectors for this process are PDE3B and ABHD15 that operated by the suppression of cAMP to attenuate pro-lipolytic PKA signaling toward adipose triglyceride lipase ATGL , hormone-sensitive lipase HSL , and perilipin PLIN.

Further, inhibition of PDE3B inhibits insulin-induced glucose uptake and antilipolysis. Insulin stimulated protein synthesis is mediated by activation of the protein kinases Akt and mTOR specifically mTORC1 and mTORC2 in numerous insulin-responsive cell types, such as hepatocytes, adipocytes, and myocytes.

Inhibition of mTOR by rapamycin obviously impairs insulin-activated protein synthesis. Amino acids metabolic substrates enhance insulin sensitivity and responsiveness of the protein synthesis system by increasing mTOR activity and inhibiting protein degradation in liver, muscle, and heart tissues.

These processes, in turn, promote protein synthesis and antagonize protein degradation. Adiponectin is the most abundant protein secreted by adipose tissue and exhibits potent anti-inflammatory properties.

Moreover, targeted disruption of AdipoR1 results in halted adiponectin-induced AMPK activation, increased endogenous glucose production and increased IR. Similarly, AdipoR2 deletion results in decreased PPAR-α signaling pathway activity and IR.

In addition, chemerin is a chemokine highly expressed in liver and white adipose tissue that regulates the expression of adipocyte genes involved in glucose and lipid homeostasis like IRS-1 tyrosine phosphorylation activity, GLUT4, fatty acid synthase and adiponectin.

Thus, chemerin may increase insulin sensitivity in adipose tissue. Leptin is a cytokine encoded by ob gene and produced by the adipocytes. In summary, adipose tissue is a central node for distinct adipokines and bioactive mediators in IR pathophysiology.

Consequently, identifying the effects of new adipokines will help in the development of new therapeutic strategies for obesity-induced diseases.

The specific insulin actions in adipose tissue include activation of glucose uptake and triglyceride synthesis, suppression of triglyceride hydrolysis and free fatty acids FFA and glycerol release into the blood circulation. Once the adipose tissue expandability exceeded limit under overnutrition, excess lipids and toxic lipid metabolites FFA, diacylglycerol, ceramide accumulated in non-adipose tissues, thus leading to lipid-induced toxicity lipotoxicity and developed IR in liver and muscle.

This process would in turn induce increased intracellular citrate levels, thereby inhibiting glucosephosphate G6P accumulation. Increased G6P levels then result in decreased hexokinase activity, increased glucose accumulation, and reduced glucose uptake.

Other studies have demonstrated the relevance of the glucose-fatty acid cycle to lipid-induced IR. For example, lipid infusions combined with heparin can be used to activate lipoprotein lipase, thereby increasing plasma concentrations of fatty acids.

Further, these infusions promote muscle lipid accumulation and effectively induce IR. Consistent with the above studies, elevated plasma fatty acid concentrations can result in increased intracellular diacylglycerol DAG levels, leading to the activation of protein kinase C isoform PKC-θ and PKC-ε isoforms in skeletal muscles and liver respectively.

Since diacylglycerol acyltransferase 1 DGAT1 can increase the conversion of DAG into triacylglycerol TAG , DGAT1 overexpression could decrease DAG levels and improve insulin sensitivity partially attenuating the fat-induced activation of DAG-responsive PKCs.

Taken together, these studies strongly support that DAG as a key intermediate of TAG synthesis from fatty acids has central modulation and potential therapeutic values in IR.

Ceramide is another specific lipid metabolite that increases in concentration, along with DAG, in association with IR in obese mice. Thus, ectopic lipid metabolite concentrations e. Consequently, concerted efforts to decrease lipid components in these organs are the most efficacious therapeutic targets for treating IR and metabolic diseases.

Some human genetic studies indicated that different genomic loci were associated with fasting insulin levels, higher triglyceride and lower HDL cholesterol levels, , which are different hallmarks of IR.

The peroxisome proliferator-activated receptor gamma PPARγ variant Pro12Ala was one of the first genetic variants identified that is involved in fatty acid and energy metabolism and that is associated with a low risk of developing T2DM.

Nevertheless, additional studies are needed to assess the functional relationships between the genetic variants and IR, that are also influenced by various lifestyle and environmental factors.

Recent studies have suggested that epigenetic modifications such as DNA methylation DNAm and histone post-translational modifications PTM are implicated in the development of systemic IR. Global and site-specific DNA methylation is generally mediated by DNA methyltransferases DNMTs. These processes mainly occur in the context of CG dinucleotides CpGs and promoter region, while also involving covalent addition or removal of methyl groups as a means to repress or stimulate transcription, respectively.

For example, increased INS promoter methylation levels and INS mRNA suppression were observed under over-nutrition conditions and obese T2DM patients. Another study demonstrated that increased IGFBP2 DNA methylation levels were are associated with lower mRNA expression levels in Visceral Adipose tissue VAT of abdominal obesity.

Moreover, the first global genome-wide epigenetic analysis in VAT from IR and insulin-sensitive IS morbidly obese patients identified a novel IR-related gene, the zinc finger protein ZNF exhibited the highest DNA methylation difference, and its methylation levels is lower in IR patient than in IS patient, consistent with increased transcription levels, such studies provide potential epigenetic biomarkers related to IR in addition to novel treatment targets for the prevention and treatment of metabolic disorders.

For example, peroxisome proliferator-activated receptor-α and -γ PPAR-α and PPAR-γ, respectively are encoded by PPARA and PPARG , respectively, and they are the two primary nuclear peroxisome proliferator-activated receptors involved in lipid metabolism.

Higher PPARA and PPARG methylation levels were observed in association with obesity, consistent with decreased PPAR-α and PPAR-γ protein expression levels, that lead to dyslipidemia and IR.

SLC19A1, a gene encoding a membrane folate carrier, was reduced in obese WAT and induced global DNA hypermethylation of chemokine C-C motif chemokine ligand 2 CCL2 that is a key factor in WAT inflammation, resulting in increased CCL2 protein secretion and the development of IR in obese.

In addition, several genes methylation involved in hypoxia stress and endoplasmic reticulum stress were regulated in obesity related metabolic diseases. Recent epigenetic genome-wide analysis identified low HIF3A methylation levels upregulates HIF3A expression in adipose tissue, thereby leading to adipose tissue dysfunction and adiposity.

Ramos-Lopez et al. Specifically, increased insulin concentrations and HOMA-IR index were accompanied by lower ERO1LB and NFE2L2 methylation levels. The histone modification effect on gene expression mainly includes histones methylation and acetylation.

Histone methylation could either activate gene transcription H3K4, H3K36, and H3K79 or silence gene expression H3K9 and H3K27 , which depends on the modification site. Histone acetylation increases the accessibility and gene expression of various transcription factors by reducing the positive charge and histone affinity for DNA.

Increasing evidence indicates , that IGFR, InsR, IRS1, Akt, GLUT4, and PPAR are more deacetylated in association with IR than in normal physiological conditions.

In contrast, IRS2, FoxO, JNK, and AMPK are usually acetylated in association with IR. Castellano-Castillo, D. Further, global proteomic analyses have revealed 15 histone modifications that are differentially abundant in hepatic IR. MicroRNAs miRNAs are small ncRNAs nucleotides incorporated into Argonaute Ago protein to form miRISCs, which can inhibit the expression of partially or completely complementary target mRMAs.

Several miRNAs are involved in β cell differentiation and mature β cell functioning. For example, islet-specific miR overexpression represses glucose-stimulated insulin secretion GSIS and insulin gene transcription, that is then reversed upon miR inhibition. Thus, these markers may improve disease prediction and prevention in individuals at high risk for T2DM.

Furthermore, pdx1, neurogenin-3 ngn3 , and a transcriptional factor essential for insulin transcription MafA are essential transcription factors for β-cell differentiation. Thus, miRa2 can directly modulate insulin expression through foxA2 and then pdx1.

miR expression is induced by the cellular redox regulator thioredoxin-interacting protein TXNIP that then represses MafA, thereby inhibiting insulin production. Numerous studies suggest that miRNAs have pivotal roles in glucose and lipid metabolism. miR was first reported to directly regulate GLUT4 expression in adipocytes.

In addition, the anti-diabetic drug metformin can up-regulate miRp expression to suppress G6Pase and inhibit hepatic gluconeogenesis. The balance of low-density lipoprotein LDL and high-density lipoprotein HDL molecules that are synthesized in hepatocytes is critical for lipid homeostasis.

Many miRNAs have been identified as critical regulators of HDL and LDL biogenesis. For example, miR, miR, miR, and miRa repress expression of the ATP-binding cassette transporter ABCA1 that mediates hepatic HDL generation.

In addition, miRc targets the gene encoding microsomal triglyceride transfer protein MTP that is required for the lipidation of newly synthesized APOB in the liver for LD lipoprotein production.

miRc overexpression reduces the assembly and secretion of these APOB-containing lipoproteins, resulting in decreased plasma LDL levels. miRa and miR repress LDLR expression and inhibition of these miRNAs results in enhanced LDLR expression and clearance of circulating LDL.

Further, miR and miRd target the LDLR chaperonin PCSK9 and IDOL in addition to the rate-limiting enzyme in cholesterol biosynthesis, HMGCR.

Chronic inflammation in insulin-reactive tissues is one of the most important causes of IR and increasing evidence suggests that miRNAs has a pivotal role in the inflammatory process. Obesity inhibited miR expression in adipose tissue macrophages ATMs , and miR was shown to target Delta-like-4 DLL4 , a Notch1 ligand is associated with ATM inflammation.

Conversely, Wang et al. discovered that miRp is significantly upregulated in Natural killer NK cells-derived exosomes from lean mice, which directly targets SKI family transcriptional corepressor 1 SKOR1 , subsequently downregulated the expression levels of pro-inflammatory cytokine factors including IL-1β, IL-6, and TNF-α levels and attenuated IR.

Therefore, it might be that metabolism-regulating miRNAs play a vital role in the dynamics of metabolic homeostasis. Long non-coding RNAs lncRNAs are non-coding transcripts more than nucleotides, and the subcellular localization of lncRNAs determines their function. LncRNAs located in the nucleus could affect chromosomal biology or interact with transcription factors to regulate gene transcription; lncRNAs located in cytosol could modulate mRNA stability and translational efficiency by acting as sponges for miRNAs or direct pairing with mRNA.

Recent advances have shown that lncRNAs play crucial roles in the pathologys of IR and diabetes. Glucose and lipid metabolism disorders are the primary causes for the pathophysiological development of IR.

The lncRNA SRA promotes insulin-stimulated glucose uptake by co-activating PPARγ, leading to increased phosphorylation of the downstream targets Akt and FOXO1 in adipocytes. These processes are closely related to the genes PGC1a and CPT1b that reverse FFA-induced lipid accumulation and improve IR.

In addition the insulin target tissues, transcriptome profiling and different studies have identified several β-cell specific lncRNAs that contribute to obesity-mediated β-cell dysfunction and apoptosis.

LncRNA MALAT1 downregulation may lead to pancreatic β-cell dysfunction and T2DM development by direct interaction and regulation of polypyrimidine bundle binding protein 1 PTBP1. Further, lncRNA-p overexpression can decrease the β cell apoptosis ratio and partially reverse the glucotoxicity effects on GSIS function.

Contrary to conventional linear RNA, circRNAs are noncoding RNAs that generated from precursor mRNAs by back-splicing circularization, which is derived from exonic circRNAs, intronic circRNAs, exonic-intronic circRNAs and ntergenic circRNAs.

Recent studies have suggested that newly identified circRNAs are novel factors in the initiation and development of IR. CircHIPK3 is one of the most abundant circRNAs in β-cells and regulates hyperglycemia and IR by sequestering miRp and miRp, thereby increasing mRNA expression of key β-cell genes e.

Similar to the miRNAs and lncRNAs, several circRNAs also contribute to the the regulation of glucose and lipid homeostasis. Deep sequencing analysis of adipose circRNA revealed that circArhgap is highly upregulated during differentiation of human white adipocytes.

Thus, circRNAs likely serve as important regulators of adipocyte differentiation and lipid metabolism. Another circRNA deep sequencing analysis of sera from patients with metabolic syndrome MetS identified the presence of a novel circRNA, circRNF, involved in MetS progression.

AMPK is a critical factor in energy homeostasis including glycolysis, lipolysis, and fatty acid oxidation FAO. CircACC1 is a circRNA derived from the human acetyl-CoA carboxylase 1 ACC1 gene and directly binds to the β and γ subunits of AMPK, facilitating its activity, and promoting glycolysis and fatty acid β-oxidation during metabolic stress.

circMAP3K4 is another potentially important circRNA involved in glucose metabolism that is highly expressed in the placentas of patients with gestational diabetes mellitus GDM and the IR model. Nevertheless, the exact roles and regulatory mechanisms of circRNAs in IR require additional clarity.

The microbes living in the human gut are key contributors to host metabolism and immune function through mediating the interaction between the host and environment, or releasing metabolites and cytokines.

Different factors influencing these alterations of gut microbiome composition have been explored including diet, exercise, circadian disruption, antibiotics treatments, and genetics.

The gut microbial communities of the groups significantly diverged over time, with participants on animal diets experiencing proliferation of bile-tolerant microorganisms e. For example, microbiome genome-wide association studies mGWAS have identified that variants of different genes for example, VDR , LCT , NOD2 , FUT2 , and APOA5 that are associated with distinct gut microbiome compositions.

Growing evidence in the last two decades has suggested that gut microbial dysbiosis contributes to increased risks of metabolic defects like obesity, IR, and diabetes.

LPS circulation then contributes to the chronic inflammation of liver and adipose tissue that is associated with the development of IR, in addition to other conditions associated with metabolic syndromes.

As we all know, IR is a state in which higher than normal concentrations of insulin are needed for a normal response, leading directly to hyperinsulinaemia and impaired glucose tolerance. Non-alcoholic fatty liver disease NAFLD is one of the most common liver diseases worldwide.

Adipose tissue is a physiologic reservoir of fatty acids, when the storage capacity is exceeded, the accumulation of heterotopic lipids leads to lipotoxicity, thereby promoting low-grade inflammation and IR in the liver. Lipotoxic injury appears to occur in response to excessive levels of serum free fatty acids FFAs in hepatocytes.

At present, the molecular mechanism of insulin in PCOS has been well described. Such modifications then activate NF-κB that is involved in the expression of proinflammatory mediators such as TNF and IL-6, , and that induces key steroidogenic molecules, like CYP11A1, CYP17A1 and StAR, leading to further aggravation of hyperandrogenemia.

Cardiovascular diseases CVDs are the leading causes of death globally. The World Health Organization estimates that Moreover, over 23 million people are estimated to die from CVDs each year by However, the most common types of CVDs include high blood pressure, coronary artery disease CAD , stroke, cerebrovascular disease and rheumatic heart disease RHD.

Identifying new therapies to reduce IR may contribute to the reduced prevalence of CVDs. Insulin primarily enters the brain via selective, saturable transport across the blood-brain barrier BBB , , Peripherally produced insulin can also be actively transported into the brain via an endocytic-exocytic mechanism.

Current researches have demonstrated that the mechanisms of systemic IR and brain-specific IR have close links with AD pathogenesis. Pioglitazone acts similarly as Rosiglitazone by reducing tau and Aβ deposits in the hippocampus, and improving neuronal plasticity and learning in AD.

Moreover, overlapping pathological features exist for diabetes, IR, and AD. Chronic kidney disease CKD involves a gradual loss of kidney function and inability to filter blood , and is a major risk factor for end-stage kidney failure ESKF and CVDs.

Numerous recent epidemiological studies have suggested that IR increases the risks for different cancers including colon, liver, pancreas, breast, endometrium, thyroid and gastric cancer.

Further, a growing body of evidence suggests that increased insulin, in addition to IGF1 and IGF2 levels critically influence tumor initiation and progression in IR patients.

As we all know, IR is related to several metabolic abnormalities including obesity, glucose tolerance, dyslipidemia, type 2 diabetes and other metabolic syndrome. Actually, IR precedes the occurrence of T2DM, so how to increase the accurate assessment of insulin sensitivity is very important to predict the risk and evaluate the management of impaired insulin sensitivity and metabolic syndrome in research and clinical practice.

HOMA2 updated HOMA model which took account of variations in hepatic and peripheral glucose resistance , homeostatic Model Assessment for IR HOMA-IR , the oral glucose insulin sensitivity index OGSI , fasting Insulin FINS , and fasting plasma glucose FPG based on fasting glucose and insulin levels , , , , are widely utilized IR measurements in clinical research.

Other indices based on fasting insulin include the glucose to insulin ratio GIR , the quantitative insulin sensitivity check index QUICKI , , , triglycerides McAuley Index alone or in accordance with HDL cholesterol HDL-C , whole-body insulin sensitivity index WBISI , Matsuda Index to evaluate whole body physiological insulin sensitivity by the above methods.

Indeed, the early symptoms of IR in different individuals are not obvious, and the related symptoms are very complex, combining with screening indicators may provide more precise diagnosis for IR in the general population.

No medications exist currently that are specifically approved to treat IR, but IR management 91 , , is possible through lifestyle changes like dietary, increased exercise, and disease prevention in addition to alternative medications Fig. Among these treatments, lifestyle changes should be the main focus for IR treatment, with nutritional intervention to decrease calories, avoidance of carbohydrates, and focusing on aliments with low glycemic index including vegetables, fruits, whole-grain products, nuts, lean meats or beans to provide higher fiber, vitamins, healthy fats and protein are particularly helpful for people trying to improve insulin sensitivity.

Table 1. Metformin is a first-line medication and the most widely-prescribed insulin-sensitizing agent in T2DM and PCOS patients. For example, 1 Glucagon-like peptide 1 GLP1 is an intestinal hormone that can enhance insulin secretion in a glucose-dependent manner by activating the GLP-1 receptor GLP-1R that is highly expressed on islet β cells.

are now world-wide therapy of T2DM since and could improve insulin sensitivity. In clinical research, scientists and physicians have explored different strategies to prevent and treat diabetes mellitus and IR.

gov to reduce IR and summarized them mainly include: 1 Diet intervention, such as Low-fat vegetarian Food, high-protein food, calorie restriction, vitamin D supplementation to reduce the IR in human obesity.

We present some clinical trials of IR intervention in Table 2. Over the past years, our knowledge of the pathogenesis of IR and T2DM has improved, the development of new treatments of IR and metabolic syndrome have gained certain success, while the complexity of IR and the presence of multiple feedback loops make a challenge to the specific intervention.

In recent years, accumulating preclinical studies on the intervention of IR have been reported, which have important reference significance for the development of new drugs.

We present the related studies on IR reported in recent years in Table 3 , including animal models, treatment methods and results.

Pre-clinical IR intervention mainly includes drug intervention, probiotic therapy and exercise supplement. Drug therapy to improve IR is the main research direction at present. Researchers found that Valdecoxib VAL can inhibit inflammation and endoplasmic reticulum ER stress through AMPK-regulated HSPB1 pathway, thus improving skeletal muscle IR under hyperlipidemia.

The researchers found that the mixed nasal administration of GLP-1 receptor agonist and L-form of peneracin can effectively alleviate the cognitive dysfunction of SAMP8 mice. Natividad et al. Regular exercise is an alternative intervention measure to maintain the blood sugar level in the normal range and reduce the risk factors.

Hsu and colleagues found that exercise combined with probiotics intervention can have a positive effect on blood sugar and increase insulin sensitivity in mice. The above results show that drug intervention, probiotic supplementation and intensive exercise can improve IR but more clinical data are still needed.

Overall, the increased incidence of IR and the key roles of IR plays in many diseases, urgently require a better understanding of IR pathogenesis in addition to how IR interacts with genetics and different environments.

A deeper understanding of IR can be achieved with a more systematic approach involving large-scale omics to study the molecular landscape is of major importance in addition to exploring new intervention strategies to prevent abnormal IR syndrome.

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Le Marchand-Brustel, Y. As with a daily calorie-restricted diet, the researchers found that both types of intermittent fasting reduced insulin resistance.

However, this type of eating had no meaningful effect on blood glucose levels, so the authors concluded that more research is necessary. In addition to changing the foods in their diet, people looking to increase their insulin sensitivity may benefit from taking dietary supplements.

Taking probiotics or omega-3 fatty acid supplements may improve insulin sensitivity in people who are overweight. A clinical trial investigated the effects of both omega-3 fatty acids and probiotics on insulin sensitivity in 60 adults who were overweight but otherwise healthy.

The researchers reported that taking either a probiotic or omega-3 supplement for 6 weeks led to significant improvements in insulin sensitivity in comparison with a placebo.

The increase in insulin sensitivity was even greater in those who took both supplements together. Learn everything you need to know about probiotics. Magnesium supplements may also be beneficial for people wanting to improve their insulin sensitivity. A systematic review found that taking magnesium supplements for more than 4 months significantly improved insulin resistance in people with and without diabetes.

Read more about magnesium glycinate, a popular supplement. Resveratrol is a natural compound that occurs in the skin of red grapes. It is also available as a dietary supplement. A meta-analysis of 11 studies found that taking resveratrol supplements significantly improved glucose control and insulin sensitivity in people with diabetes.

However, the researchers did not observe the same effects in people without diabetes. They concluded that there is a need for more research on the effects of resveratrol supplementation in humans.

Low insulin sensitivity is a risk factor for developing type 2 diabetes. Exercising well, getting enough sleep, and eating a nutritious diet high in unsaturated fats and soluble fiber may help improve insulin sensitivity in people with and without diabetes.

Certain dietary supplements may also be beneficial. Many of these supplements are available to purchase online:. However, a person should be aware that the Food and Drug Administration FDA does not regulate supplements.

Therefore, they should speak with their doctor before taking any supplement. Individuals can discover more resources for living with type 2 diabetes by downloading the free T2D Healthline app.

It provides access to expert content and peer support through one-on-one conversations and live group discussions. Download the app for iPhone or Android. Find out here about the differences and….

Many people avoid eating carbohydrates to help them lose weight. However, some carbohydrates are beneficial and can be healthful when included in the….

A study in mice suggests a potential mechanism that could explain why only some individuals with obesity develop type 2 diabetes.

A type of medication used to treat type 2 diabetes could help lower the risk of developing kidney stones, a new study suggests. Some recent evidence suggest that 4 grams of cinnamon per day, in the form of supplements, could help lower blood sugar levels in people with obesity….

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In the present study, we present a proof of concept of how an optimization process based on an evolutionary algorithm EA allows to determine the optimal pattern of dietary intake and the optimal insulin doses for patients with T2DM administering insulin therapy treatment. We optimized these parameters according to the characteristics of each patient, with three specific objectives: i to prevent episodes of hypoglycemia, ii to minimize the severity of hyperglycemia, and iii to minimize the insulin requirement.

It is worth noting that despite the extensive study of the use of AI techniques in diabetes Li et al. To evaluate the use of EAs for the optimization of the control of T2DM, a mathematical model was used to describe the physiology of a virtual patient with T2DM. The use of mathematical models in preclinical trials is becoming increasingly widespread because they accelerate the development of new therapies.

For example, the US Food and Drug Administration accepts a DM1 simulator as a substitute for preclinical trials for certain insulin therapies, including a closed-loop algorithm for use with an artificial pancreas Dalla Man et al.

The model used in the present study was an adaptation of the model developed by Visentin et al , involving a basal insulin infusion and a prandial insulin bolus.

The parameters included permit individuals with differing severities of T2DM to be modeled. We developed the EA with the objective of determining the optimal daily food intake pattern and optimal insulin therapy such as prandial insulin in combination with basal insulin administration , and minimizing the total insulin dose required.

To evaluate the effects of differing intake patterns on glycemic control in silico , we implemented a mathematical model that described the physiology of patients with T2DM, based on the model developed by Visentin et al The model described glucose transit through the gastrointestinal tract, the effects of insulin on glucose utilization and production, and the control of insulin secretion by glucose.

The model constructed was a combination of submodels that describe various processes Supplementary Figure S1. Specifically, the submodels included within the model constructed were as follows: 1 the glucose subsystem, 2 intestinal glucose absorption, 3 renal glucose excretion, 4 endogenous glucose production, 5 glucose use, and 6 the insulin subsystem.

For simplicity, the C-peptide secretion system was not considered because does not have backward regulations affecting the other systems involved see Figure 2 in Visentin et al The Supplementary material contains a detailed description of all the subsystems considered and the parameters used in the simulations.

In the present study, a subcutaneous insulin subsystem was added to this model to simulate subcutaneous insulin infusion and prandial administration, according to the model developed by Schiavon et al. It should be noted that this model provides a description of patients with T2DM and a range of levels of insulin production and insulin resistance, which depend on their i levels of peripheral and hepatic insulin sensitivity, ii level of β -cell responsivity, and iii basal circulating insulin and glucose concentrations.

Three individuals with differing severity of T2DM were studied: T2DMA, corresponding to a person with prediabetes, and T2DMB and T2DMC, corresponding to patients with intermediate and advanced stages of diabetes, respectively. The parameters used to describe these individuals were as follows: i basal insulin Ib , ii basal glucose Gb , iii insulin-dependent glucose utilization Vmax , iv pancreatic responsivity to the glucose rate of change K , v pancreatic insulin secretion β , and vi the response of the liver to insulin with respect to endogenous glucose production kp3.

Table 1 shows the parameters of each of these individuals. The rest of parameters are shown in Supplementary Table S1. To achieve the objective of identifying a dietary intake pattern that optimizes glucose control and minimizes the insulin dose, we implemented an EA that includes the following:.

The total dietary intake throughout the day, resulting in the liberation of g of glucose by digestion. A maximum of five meals for each pattern. Finally, the meal pattern P j was combined with a basal infusion of insulin I B j from a pump.

Combinations of diet, prandial insulin, and basal insulin, i. This fitness function was defined as follows:. Here, G min and G max are the minimum and maximum plasma glucose concentrations during the day, G 0 t is the target minimum value for plasma glucose, and G 1 t is the target 2 h postprandial plasma glucose concentration.

The first term f L represents the difference between the real minimum plasma glucose concentration and the optimum concentration G t , the second term is the maximum change in plasma glucose induced by each meal, the third term is the basal insulin dose, and the final term is the total prandial insulin dose administered during a day.

The parameters μ 1 , μ 2 , and μ 3 correspond to the weightings of the contribution of each of these terms to the f j function.

The objective of the EA was to minimize this fitness function. To this end, it included the following steps:. Step 1: The N elements Ψ j were initially randomly determined the size of each meal Q i j , the time of meal ingestion T i j , the dose of prandial insulin D i j , and the level of the basal infusion I B j.

Step 2: For each of the individuals described in Table 1 , all the combinations of Ψ j were applied, and the physiological responses were computationally simulated. Step 3: The fitness function f j was calculated for each Ψ j.

Step 4: The Ψ j combinations were sorted from the lowest to highest values of f j. If two or more combinations had the same values of f j , they were sorted from the lowest to highest dose of total insulin administered, i.

Step 6: A new set of Ψ j was generated. These new combinations were the result of the duplication Ψ j randomly chosen with probability η j from those selected in step 5, along with random mutations.

The probability of selection was calculated as follows:. Once a combination Ψ j was selected, an element of the set { Q i s , T i s , D i s , I B s } was randomly selected to be mutated with equal probability.

Where the element to be mutated was the size of the meal, i. Table 2 summarizes the rules for the mutation. Step 6 was repeated until a group of N combinations was compiled, which was used to configure the next-generation of the evolutionary process.

Subsequently, the algorithm returned to step 2 and was repeated until the maximum number of generations was reached.

It should be noted that this EA did not include crossover between Ψ j combinations because it is necessary to ensure that the total food intake remained constant.

Supplementary Figure S2 summarizes the different steps involved in this evolutionary process. To study the utility of EAs for the optimization of dietary intake and insulin dose necessary to facilitate glycemic control, three individuals with differing severities of T2DM were considered: T2DMA, T2DMB, and T2DMC, plus a healthy individual as a reference.

The parameters defining the characteristics of each individual are presented in Table 1. The remaining model parameters were identical for T2DMA, T2DMB, and T2DMC Supplementary Table S1. Figure 1A shows the glucose curves obtained for individuals following the consumption of g of glucose in the absence of exogenous insulin administration.

This figure shows in gray the zone considered to represent normoglycemia, according to the ADA criteria, and prior to the glucose load, the plasma glucose levels of the participants should have been within this zone.

The simulation results presented in Figure 1A show differing degrees of deviation from the ADA criteria, corresponding to differing severities of diabetes. It can be seen how the individual T2DMA showed poor glucoregulation following food intake but acceptable basal plasma glucose concentrations within the gray area , corresponding to prediabetes.

The individuals T2DMB and T2DMC showed poorer regulation of both basal and postprandial glucose concentrations. FIGURE 1. Plasma glucose concentration curve following the ingestion of g glucose. Plasma insulin concentration curve following the ingestion of g glucose. T2DMA orange line , T2DMB yellow line , and T2DMC blue line : individuals with increasing severity of type 2 diabetes.

Figure 1B shows the plasma insulin concentrations of these individuals. Their plasma insulin concentrations were found to be higher than in healthy individuals as a result of insulin resistance.

However, these concentrations decreased as glucose regulation worsened, which implies that in addition to insulin resistance, there was a reduction in the ability of the individuals to secrete insulin, corresponding to a worsening of diabetes.

The EA described in the Materials and methods section was used to determine the food intake pattern that would minimize the dose of insulin, both basal and prandial, necessary to achieve good glucoregulation, according to the ADA criteria.

In the first set of simulations, the EA was permitted to introduce random mutations with respect to both the insulin dose and the timing and size of each meal.

Specifically, in each simulation, the consumption of a meal was regarded as taking 20 min Supplementary Equation S4 , basal insulin was assumed to be supplied using an insulin pump at a constant infusion rate during the day, and prandial insulin was assumed to be injected 15 min before food intake Supplementary Equation S9.

In all the simulations performed, the total amount of glucose consumed during each day was g, distributed across up to five meals. These meals were stipulated to be consumed within a maximum of a 14 h period.

The simulations were conducted over generations, after which the results had clearly stabilized. Figure 2 shows the results of the first set of simulations. Figures 2A—C show the evolution of the fitness function over successive generations for the three individuals. As shown in the figures, after generations, the fitness function was stable.

These parameters were determined in multiple preliminary simulations to be those that permit the EA to find the best solution. The inset figures represent the minimum blue line and maximum red line plasma glucose concentrations 2 h after a meal, and the gray area represents the optimal basal glucose concentrations for patients with diabetes.

FIGURE 2. Evolution of the fitness function over generations for the three individuals studied gray line. A T2DMA, B T2DMB, and C T2DMC. Inset figures represent the minimum blue line and maximum red line plasma glucose concentrations 2 h following meal consumption.

The gray area represents the optimal basal glucose concentrations for patients with diabetes, according to the American Diabetes Association criteria. The minimization of the fitness function was associated with that of the amount of insulin required to control glycemia, as shown in Figure 3.

Figures 3A—C show the evolution of the basal insulin doses provided to ensure optimal glucose concentrations prior to a meal for the three individuals analyzed.

In addition, Figures 3D—F show the evolution of the prandial insulin doses administered. Initially, the doses of prandial insulin were high in the three individuals analyzed.

However, as the dietary intake patterns were modified by the EA see Supplementary Figures S3, S4 , and Supplementary Figures S5 , superior regulation could be achieved alongside a reduction in the amount of insulin required.

It is important to note that in the case of the individual T2DMA, the solution provided by the algorithm did not require the administration of exogenous insulin.

The optimal distribution of food intake throughout the day was sufficient to achieve a good level of regulation of glycemia in this individual, whereas the individuals T2DMB and T2DMC required increasing doses of both basal and prandial insulin, according to the severity of T2DM exhibited by each individual.

FIGURE 3. Evolution of the total insulin dose required for the three individuals analyzed. Evolution of the basal insulin dose for T2DMA blue line. Evolution of the basal insulin dose for T2DMB blue line.

Evolution of the basal insulin dose for T2DMC blue line. Evolution of the prandial insulin dose for T2DMA red line.