Hyperglycemia and insulin sensitivity -
If glucose levels are higher than usual but not high enough to indicate diabetes , doctors call this prediabetes. Prediabetes often occurs in people with high insulin resistance.
Around 1 in 3 people in the United States have prediabetes, according to figures from the Centers for Disease Control and Prevention CDC. In this article, we look at the current understanding of insulin resistance and its role as a risk factor for diabetes and other conditions. We also describe the signs and symptoms of insulin resistance and ways to avoid it.
Insulin resistance is when cells in the body do not respond properly to the communication signals from insulin. This increases the risk of developing prediabetes and, eventually, type 2 diabetes. If the pancreas can make enough insulin to overcome the low rate of absorption, diabetes is less likely to develop, and blood glucose will stay within a healthy range.
Over time, the pancreas loses its ability to release insulin, and this can lead to the development of type 2 diabetes.
Insulin regulates the amount of glucose that circulates in the bloodstream. It induces the cells to absorb glucose, which comes from the food people eat. Insulin is also the chemical messenger that instructs the liver to store some glucose, rather than release it into the bloodstream.
The liver packages glucose for storage in the form of glycogen. Insulin usually helps the body maintain a good balance of energy, not allowing the level of blood glucose to spike for too long. The following steps outline the current understanding of how insulin resistance develops:.
Insulin resistance does not usually present symptoms until diabetes develops. If someone has concerns about these conditions, they may wish to consider seeking a test for insulin levels and insulin resistance. The following are risk factors for insulin resistance, prediabetes, and diabetes:.
Prediabetes and diabetes have some risk factors in common with heart disease and other cardiovascular and cerebrovascular health problems, such as stroke. It is not always possible to prevent these risk factors, but some may be avoidable.
For this reason, doctors encourage lifestyle measures that can help reduce the risk of the condition. The Department of Health and Human Services recommends that everyone over 45 years of age receive testing for diabetes.
Learn why diabetes is more likely to affect African Americans here. If blood sugar levels consistently fall outside of a normal range, it might indicate that the body is becoming resistant to insulin.
It is not possible to change some risk factors for insulin resistance and type 2 diabetes, such as genetic factors and family history. Oral glucose tolerance test OGTT : OGTT, a mainstay in the diagnosis of impaired glucose tolerance IGT and diabetes mellitus in pregnant and nonpregnant women, may be used to assess insulin sensitivity as well.
Because no IV access is needed, OGTT is better suited for assessment of large populations than the other techniques we outlined. A modified OGTT that uses a or g glucose load and measures glucose and insulin at various intervals over 2 to 4 hours has been used in clinical studies.
Like other minimal approaches to diagnosis, OGTT provides information on beta cell secretion and peripheral insulin action, and various mathematical equations have been used to provide an SI value.
Insulin resistance has also been assessed qualitatively if one or more insulin values exceed an upper limit of normal at appropriate intervals. Researchers have compared various methods for assessing insulin sensitivity in type 2 diabetics using the OGTT and found good correlations between AUCinsulin, insulin level at minutes I , and the steady state plasma glucose concentrations derived from a modified ITT.
As mentioned before, the search for uncomplicated and inexpensive quantitative tools to evaluate insulin sensitivity has led to development of fasting state homeostatic assessments.
These tests are based on fasting glucose and fasting insulin, and use straightforward mathematical calculations to assess insulin sensitivity and beta cell function. Several homeostatic approaches have been developed in recent years, each with its merits and deficiencies.
One of the weaknesses of these models is that they assume the relationship between glucose and insulin is linear when in fact it's parabolic. Fasting insulin I0 : Fasting serum insulin is an inexpensive assay, and does not require any mathematical calculations.
At least one researcher has advocated averaging two or three readings to account for day-to-day variability. Although I0 is less variable than other fasting procedures in normoglycemic patients, clinicians must still interpret results cautiously. Remember that insulin sensitivity is the ability of the hormone to reduce serum glucose.
If fasting glucose is high—for example, in a patient with impaired glucose tolerance—that may indicate a diminished effect from circulating insulin or in severe cases of insulin resistance, diminished quantity of the hormone.
Hence I0 should not be used in glucose-intolerant or diabetic patients. The ratio of glucose to insulin is easily calculated, with lower values depicting higher degrees of insulin resistance. Homeostatic model assessment HOMA : HOMA has been widely employed in clinical research to assess insulin sensitivity.
The constant should be replaced by The HOMA value correlates well with clamp techniques and has been frequently used to assess changes in insulin sensitivity after treatment. Quantitative insulin sensitivity check index QUICKI : Like HOMA, QUICKI can be applied to normoglycemic and hyperglycemic patients.
It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin:. Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well.
As the SI decreases, QUICKI values increase. McCauley et al. An ISI of 6. The authors present two formulae for estimating ISI; one uses I0, BMI, and TG, and the other uses only I0 and TG.
In comparisons with the euglycemic insulin clamp technique the first formula with BMI has a specificity of 0. The second forumula without BMI has a specificity of 0. Her hemoglobin A1c ranged between 5. Following admission, her course was complicated by significant difficulty with oxygenation, pneumomediastinum due to barotrauma and acute kidney injury.
She was ultimately transferred to our institution for extra-corporeal membrane oxygenation ECMO from an outside hospital. On arrival at our hospital, she received 1 dose of sarilumab human monoclonal antibody against interleukin-6 IL-6 and was started on IV methylprednisolone.
Subcutaneous insulin was initiated simultaneously to assist in weaning off the insulin infusion as rapidly as possible. This protocol has recently been published in Gianchandani et al.
Her hour insulin requirements peaked at 6. After discontinuation of methylprednisolone her insulin requirements decreased significantly, her insulin infusion was titrated off and subcutaneous insulin was decreased to Lantus 25 units twice daily and regular insulin 48 units every 6 h.
Despite this improvement, she did continue to require over units of insulin daily via subcutaneous injection even after discontinuation of the methylprednisolone. Six days after methylprednisolone discontinuation, her insulin requirements dropped precipitously, which coincided with ECMO decannulation.
Insulin was discontinued completely 12 days later. She continued to require mechanical ventilation for over 2 months and was discharged to a long-term care facility for further ventilator weaning. Six months after discharge from the hospital, her creatinine had not yet returned to baseline, but had improved to 1.
Her hemoglobin A1c at that time was 5. She had successfully been liberated from the ventilator and returned home. Over the last year, a picture has emerged that illustrates the increased risk of severe infection and death in patients with diabetes who develop COVID Patients with diabetes are more likely to require hospitalization and ICU admission and have a higher risk of death than those without diabetes [ 2 , 3 , 4 ].
Here we present the cases of two patients with a history of diabetes that developed COVID, difficult to control hyperglycemia and severe insulin resistance, prompting us to consider the mechanisms underlying the poor prognosis for patients with diabetes and how glucose control and insulin treatment might interact with this infection.
Prior to the COVID pandemic, there was already a wealth of data demonstrating that hyperglycemia and insulin resistance during critical illness is associated with worse outcomes [ 7 , 8 , 9 , 10 ].
Extreme insulin resistance is most often seen in the setting of rare genetic disorders such as lipodystrophy and severe insulin resistance syndrome, use of medications such as glucocorticoids or endocrinopathies such as Cushings [ 5 ].
As dexamethasone is one of the few treatments that decreases mortality in severe COVID infection [ 11 , 12 ], this is likely a significant contributor to the severe hyperglycemia in many patients with COVID However, it is not the only cause, as the first patient described in this report developed severe hyperglycemia and insulin resistance despite never receiving steroids.
Similarly, the second patient continued to have severe insulin resistance for 6 days following discontinuation of steroids. Acute infections also lead to increased insulin resistance through enhanced secretion of the counter-regulatory hormones cortisol, glucagon and growth hormone [ 13 ].
In addition to the hormonal response to stress, cytokine expression may independently contribute to increasing insulin resistance during infection [ 14 ]. Thus, the robust inflammatory response in patients with SARS-CoV-2 could be a significant contributor to their severe insulin resistance [ 6 ], as both of our patients had elevated inflammatory markers that coincided with increasing insulin demands Table 1.
The interaction between insulin resistance, severe hyperglycemia and inflammation is likely to be particularly important in the setting of SARS-CoV-2 infection, as the robust inflammatory response has been linked to poor outcomes [ 15 ]. In patients with diabetes who present with COVID, the inflammatory marker C-reactive protein CRP has been identified as one of the strongest risk factors for mortality [ 2 ], while patients with prolonged hyperglycemia have higher IL-6 and D-dimer levels and a higher risk of progressing to severe disease [ 16 ].
While inflammation leads to hyperglycemia and insulin resistance, hyperglycemia and insulin resistance also exacerbate inflammation, impair immune cell function and promote epithelial cell dysfunction, even in otherwise healthy volunteers [ 17 , 18 , 19 , 20 , 21 ]. Treatment of hyperglycemia in patients with COVID has been particularly difficult as many centers have attempted to limit insulin infusions to preserve PPE and minimize health care provider exposure, as treatment with insulin infusion require hourly finger stick blood glucose checks.
Given the extraordinary doses of insulin required in the patients presented here, it is valuable to consider the potential effects of insulin beyond its hypoglycemic effects, and in particular, its role in inflammation. When evaluated in the setting of obesity-related insulin resistance, high doses of insulin may be pro-inflammatory.
In both obese mice and humans, hyperinsulinemia results in elevated adipose tissue cytokine levels [ 22 , 23 , 24 , 25 ], while this does not occur in healthy, non-obese and non-insulin resistant patients [ 26 ].
In contrast, many studies have demonstrated that insulin treatment in the setting of sepsis is anti-inflammatory. In multiple animal models of infection, insulin treatment decreases systemic cytokines independent of glucose levels [ 27 , 28 , 29 ].
This finding holds true in human studies as well. In healthy patients with both type 1 and type 2 diabetes, insulin infusion with dextrose to maintain euglycemia leads to decreased reactive oxygen species, systemic cytokine gene expression and serum CRP levels [ 30 , 31 , 32 ].
Based on our review of the literature and exemplified by the cases presented here, it is likely that hyperglycemia in patients with COVID infection worsens the dramatic inflammation and cytokine storm that accompanies severe infection.
Insulin treatment reduces blood glucose levels and may have an anti-inflammatory action in the setting of COVID sepsis. Data sharing is not applicable to this case report as no datasets were generated or analyzed during the current study.
For the CORONADO investigators. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, et al. Phenotypic characteristics and prognosis of inpatients with COVID and diabetes: the CORONADO study.
Diabetologia [Internet]. Chen Y, Yang D, Cheng B, Chen J, Peng A, Yang C, et al. Clinical Characteristics and Outcomes of Patients With Diabetes and COVID in Association With Glucose-Lowering Medication. Diabetes Care. Kumar A, Arora A, Sharma P, Anikhindi SA, Bansal N, Singla V, et al.
Is diabetes mellitus associated with mortality and severity of COVID? A meta-analysis. Diabetes Metab Syndr Clin Res Rev. Zhu L, She Z-G, Cheng X, Qin J-J, Zhang X-J, Cai J, et al.
Association of Blood Glucose Control and Outcomes in Patients with COVID and Pre-existing Type 2 Diabetes. Cell Metab. Ovalle F. Clinical approach to the patient with diabetes mellitus and very high insulin requirements.
Diabetes Res Clin Pract. Article CAS Google Scholar. Gianchandani R, Esfandiari NH, Ang L, Iyengar J, Knotts S, Choksi P, et al. Managing Hyperglycemia in the COVID Inflammatory Storm. Early insulin resistance in severe trauma without head injury as outcome predictor? A prospective, monocentric pilot study.
Scand J Trauma Resusc Emerg Med. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview.
Article Google Scholar. Lazzeri C, Bonizzoli M, Cianchi G, Ciapetti M, Socci F, Peris A. The prognostic role of peak glycemia and glucose variability in trauma: a single-center investigation. Acta Diabetol.
Brealey D, Singer M. Hyperglycemia in critical illness: a review. J Diabetes Sci Technol. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID The CoDEX Randomized Clinical Trial.
The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid — Preliminary Report. N Engl J Med.
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