Use of U-500 insulin in the treatment of severe insulin resistance

Background: Glycemic control is essential in the management of diabetes. However, many patients with diabetes are not achieving therapeutic targets, partly because they are receiving insufficient doses of insulin. This is particularly problematic in patients with severe insulin resistance, defined as insulin requirement >200 units/kg per day (>3 units/kg per day for pediatric patients). It is difficult to use U-100 forms of insulin at doses >200 units/kg per day because of the volume of insulin being administered subcutaneously. U-500, a concentrated form of insulin, may be useful in the treatment of these patients.Objective: Current practice regarding the use of U-500 insulin has been published elsewhere. This article presents an updated algorithm for the administration and dosing of U-500 insulin, based on clinical experience with severe forms of insulin resistance. Guidelines are provided for dose escalation of U-500 insulin.Methods: We reviewed the results of treatment with U-500 insulin in patients with severe insulin resistance. We analyzed the results, updated a pre-existing algorithm, provided additional practical information on the administration and dosing of U-500 insulin, and compared the cost of U-500 with that of U-100 insulin.Results: To date, we have treated 56 patients (age range, 9–54 years) with severe insulin resistance using U-500 insulin. Doses ranged from 1.5 to 566 units/kg per day. Based on the pharmacodynamic properties of U-500 insulin, this concentrated form must be administered and dosed differently than regular U-100 insulin. U-500 insulin cost more than U-100 insulin on a per-milliliter basis, but cost less in the end because of the lower volumes of insulin required and fewer syringes and pump cartridges needed to administer U-500 insulin.Conclusions: In our experience, U-500 insulin is a useful tool in the management of patients with severe insulin resistance. U-500 insulin alleviates the volume-related problems associated with U-100 insulin, making treatment with higher doses of insulin (≥200 units per day) more effective with U-500 insulin than with U-100 insulin.     

Transient extreme insulin resistance in shock during diabetic ketoacidosis.

Transient extreme insulin resistance was encountered during an episode of diabetic ketoacidosis (DKA) in an insulin-treated diabetic patient. On admission, the plasma glucose level was 1241 mg dl-1 and arterial blood pH 6.895 with HCO3- 4.7 mEql-1. An intravenous bolus injection of 20 units, followed by continuous infusion of 20 units h-1 of short-acting regular human insulin, was instituted. Ischemic myocardial changes were noted on the initial electrocardiogram, therefore fluid replacement was limited to 1,000 ml of 0.9% saline solution in the first hour. As the plasma glucose level declined by only 203 mg dl-1 (41 mg dl-1 h-1) in the first 5 h, the insulin dose was doubled every 2 h. At hour 4, the patient developed circulatory shock which required vasopressor support and respiratory assistance. A plasma glucose level of 300 mg dl-1 was not achieved until the total dosage of insulin amounted to 91,580 units at hour 25. Insulin resistance was not observed from that point on. The patient had neither insulin antibodies nor anti-insulin receptor antibodies in serologic testing. The insulin binding characteristics of the patient's erythrocytes were similar to those from healthy controls both with and without experimental acidosis and with a high level of beta-hydroxybutyrate. Among multiple potential factors, the severe shock associated with DKA has been considered as a primary cause of the transient severe insulin resistance in this case.     

Breastfeeding and the Basal Insulin Requirement in Type 1 Diabetic Women

ObjectiveTo evaluate whether breastfeeding in women with type 1 diabetes mellitus is associated with a decreased insulin requirement.MethodsIn this prospective study conducted between September 2006 and August 2008, type 1 diabetic pregnant women were recruited before the third trimester of pregnancy. Eligible women had no evidence of diabetes-related complications and were treated with continuous subcutaneous insulin infusion pump therapy. During pregnancy and in the first 8 weeks of the postpartum period, participants performed daily fingerstick blood glucose monitoring with at least 12 measurements per day; insulin dosages were adjusted to maintain normoglycemia. Participant characteristics, diabetic parameters, and neonatal growth were compared between women who breastfed exclusively and women who did not breastfeed.ResultsOf 18 women, 12 breastfed and 6 did not. Compared with nonbreastfeeding mothers, breastfeeding mothers showed a decreased need for total daily basal insulin (0.21 ± 0.05 units/kg per day vs 0.33 ± 0.02 units/kg per day). The mean value of total daily basal insulin was significantly lower in the breastfeeding group than in the nonbreastfeeding group. The mean number of hyperglycemic episodes in the first 2 weeks post partum and during the third to eighth weeks was not different between the groups.However, the mean number of hypoglycemic episodes in the first 2 weeks post partum in the breastfeeding group was significantly higher than in the nonbreastfeeding group (11.9 ± 2.6 episodes vs 5.5 ± 1.6 episodes, P < .001). No differences were observed between the groups in neonatal birth weight or infant weight after 8 weeks of age.ConclusionsDecreased need in total daily basal insulin is caused by increased glucose use during lactation. We recommend that the starting total daily basal insulin dosage for type 1 diabetic women who breastfeed be calculated as 0.21 units times the weight in kg per day. This regimen results in normoglycemia and minimizes the risk of severe hypoglycemia associated with lactation. (Endocr Pract. 2009;15:187-193)     

Insulin sensitivity regulated by feeding in the conscious unrestrained rat

Hepatic insulin sensitizing substance (HISS), a putative hormone released from the liver in response to insulin in fed animals, accounts for 50-60% of insulin action. HISS release is regulated by permissive control of the hepatic parasympathetic nerves. The objectives were to develop the rapid insulin sensitivity test (RIST) in conscious rats, and to assess the effects of anesthesia, atropine, feeding, and fasting on insulin action. The RIST index, expressed as milligrams glucose per kilogram body weight required to maintain euglycemia after a 50 mU/kg bolus of insulin, was similar in conscious and anesthetized rats (238.6+/-42.5 vs. 225.3+/-30.4 mg/kg). Atropine produced a 56% inhibition of insulin action in fed rats. After a 24 h fast, full HISS-dependent insulin resistance had developed as shown by a low RIST index that was not reduced further by atropine. Fasting caused a 10.5% decrease in insulin action per hour over six hours. HISS-dependent insulin resistance in 24-h fasted rats was reversed 4 h after re-feeding (90.9+/-12.3 vs. 204.5+/-30.5 mg/kg). We conclude that HISS-dependent and HISS-independent insulin action, as assessed by the RIST, is similar in conscious and pentobarbital-anesthetized rats. Pharmacological blockade of HISS-dependent insulin action and physiological regulation of HISS action by feeding-fasting is confirmed. Re-feeding fasted rats reversed HISS-dependent insulin resistance. Merits of use of the RIST in conscious versus anesthetized rats are discussed.     

INTRAVENOUS NUTRITION—A Clinical Evaluation of a 50 Per Cent Dextrose in Water Solution,Containing 1 mg. of Hydrocortisone per 100 ml

A 50 per cent dextrose in water solution, containing 1 mg. of hydrocortisone per 100 ml., was used successfully in 70 patients for intravenous nutritional maintenance and repletion. There were no adverse systemic effects during or following 216 infusions. The only undesirable local reaction was the rare occurrence of pain in the arm when the concentrated solutions were given too rapidly. Glycosuria was minimal if the infusion rate did not exceed 0.85 gm. of glucose per kilogram of body weight per hour, particularly if 50 units of insulin were added to each 550 ml. bottle of 50 per cent dextrose. In patients without significantly elevated serum potassium content, 30 mEq. of potassium chloride, acetate or phosphate was added to each bottle to prevent hypokalemia.Preliminary observations suggest that this new solution may be given safely intravenously, without need for cutdowns or plastic catheters, if the needle is carefully inserted and well immobilized in the arm vein and the duration of the infusion is not too prolonged. Further studies on the effect of such high caloric supplementation plus protein hydrolysates in parenteral nutritional repletion and maintenance are indicated.     

Significance of Hyperamylasaemia and Abdominal Pain in Diabetic Ketoacidosis

An analysis of 35 consecutive episodes of diabetic ketoacidosis confirmed the frequent high levels of serum amylase in this condition. Serum amylase was raised during 21 episodes (60%), and in six instances (17%) the peak level exceeded 1,000 Somogyi units per 100 ml. Hyperamylasaemia was more often found when the initial blood sugar exceeded 500 mg/100 ml, or when the onset of the episode had been relatively acute (less than 48 hours). There was no conclusive evidence in any patient to support a diagnosis of acute pancreatitis and other explanations for the hyperamylasaemia are discussed. Even grossly raised amylase levels were not associated with increased mortality or morbidity.     

Effect of hypoglycemia on the brain free fatty acid level and the uptake of fatty acids by phospholipids

The effect of hypoglycemia on the uptake of [1-¹⁴C]arachidonate and [1-¹⁴C]oleate into a synaptosomal and microsomal glycerophospholipids was investigated. In the presence of ATP, Mg²⁺ and CoA, rat brain synaptosomes and micorsomes catalyze the transfer of arachidonate and oleatc into glycerophospholipids. Arachidonate was mainly incorporated into phosphatidylinositol (PI) and phosphatidylcholine (PC), whereas oleate was incorporated into phosphatidylcholine and phosphatidylethanolamine (PE).Hypoglycemia was produced by intraperitoneal injection of 10 or 100 units of crystalline insulin per kg body weight. Two hours after injection the blood glucose level decreased to 10–20 mg%. The content of brain phospholipids was slightly decreased but the change was not statistically significant. The level of free fatty acids (FFA) was increased. More pronounced and reproducible changes were found when hypoglycemia was produced by injection of 100 units of insulin per/kg body weight. Changes in brain cortex were similar to those observed in microsomes and synaptosomes. Hypoglycemia affected the incorporation of arachidonic acid into glycerophospholipids of brain membranes. Uptake of [1-¹⁴C]arachidonate was decreased selectively by 50% (into phosphatidic acid /PA/) when hypogiycemia was produced by injection of 10 units of insulin per kg body weight. The Higher dose of insulin 100 units per kg body weight produced a 20% inhibition of arachidonate incorporation into synaptosomal PI and a 13% decrease of incorporation into microsomal phosphatidylcholine. Incorporation of [1-¹⁴C]oleate into membrane phospholipids was not changed by hypoglycemic insult. It is proposed that the disturbances in fatty acid level, particularly arachidonate, and decreased uptake of arachidonic acid by synaptosomal glycerophospholipids may be responsible for alteration of membrane function and changes of synaptic processes.     

High-dose Insulin Therapy: is it Time for U-500 Insulin?

ObjectiveTo provide an overview of U-500 regular insulin action, review published clinical studies with U- 500 regular insulin, and offer guidance to practicing endocrinologists for identifying patients for whom U-500 regular insulin may be appropriate.MethodsThis review has been produced through a synthesis of relevant published literature compiled via a literature search (MEDLINE search of the English-language literature published between January 1969, and July 2008, related to U-500, insulin resistance, concentrated insulin, high-dose insulin, insulin pharmacokinetics, and diabetes management) and the authors’ collective clinical experience.ResultsThe obesity epidemic is contributing to an increase in the prevalence of type 2 diabetes, as well as to increasing insulin requirements in insulin-treated patients. Many of these patients exhibit severe insulin resistance, manifested by daily insulin requirements of 200 units or greater or more than 2 units/kg. Delivering an appropriate insulin volume to these patients can be difficult and inconvenient and may be best accomplished with U-500 regular insulin by multiple daily injections or with continuous subcutaneous insulin infusion, rather than with standard U-100 insulin. Implementation of U-500 regular insulin in patients previously on other insulin formulations is described with a treatment algorithm covering dosage requirements ranging from 150 to more than 600 units per day on the basis of the authors’ experience.ConclusionRegimen conversion of appropriately selected patients from high-dose, U-100 insulin to U-500 regular insulin therapy on the basis of the recommendations presented in this article may potentially result in improved glycemic control and lower cost. (Endocr Pract. 2009;15:71-79)     

Assessment of Insulin Infusion Requirements in COVID-19-Infected Patients With Diabetic Ketoacidosis

Background/ObjectiveCoronavirus disease 2019 (COVID-19) is thought to contribute to diabetic ketoacidosis (DKA) and worse outcomes in patients with diabetes. This study compared the cumulative insulin dose required to achieve DKA resolution in the intensive care unit among patients with type 2 diabetes and COVID-19 infection versus without COVID-19 infection.MethodsThis retrospective cohort study evaluated 100 patients—50 patients with COVID-19 in cohort 1 and 50 patients without COVID-19 in cohort 2—treated with insulin infusions for DKA at a tertiary care teaching hospital. The primary outcome was to compare the cumulative insulin dose required to achieve DKA resolution in each cohort. The secondary outcomes included time to DKA resolution, mean insulin infusion rate, and mean weight-based cumulative insulin infusion dose required to achieve DKA resolution. All endpoints were adjusted for confounders.ResultsThe mean cumulative insulin dose was 190.3 units in cohort 1 versus 116.4 units in cohort 2 (P = .0038). Patients receiving steroids had a mean time to DKA resolution of 35.9 hours in cohort 1 versus 15.6 hours in cohort 2 (P = .0014). In cohort 1 versus cohort 2, the mean insulin infusion rate was 7.1 units/hour versus 5.3 units/hour (P = .0025), whereas the mean weight-based cumulative insulin infusion dose was 2.1 units/kg versus 1.5 units/kg (P = .0437), respectively.ConclusionCOVID-19-infected patients required a significantly larger cumulative insulin dose, longer time to DKA resolution, higher insulin infusion rate, and higher weight-based insulin infusion dose to achieve DKA resolution versus non–COVID-19-infected patients with type 2 diabetes.     

Insulin,Glucose, and Potassium in the Treatment of Congestive Heart Failure

A daily infusion of 500-1,000 ml of 50% glucose containing 100-120 units of soluble insulin and 100-120 mEq of potassium chloride per litre was given to six patients suffering from hyponatraemia and congestive cardiac failure resistant to digoxin and diuretic therapy. In two patients there was no response, but four showed a striking improvement with a sodium and water diuresis, a rise in plasma sodium level, and in two cases a reversion from atrial fibrillation to sinus rhythm. It is suggested that insulin, glucose, and potassium given by the intravenous route in adequate dosage forms a useful adjunct to the management of severe congestive heart failure.     

The erythrocyte insulin receptor response to insulin induced hypoglycaemia

The response of the erythrocyte insulin receptor to a prolonged intravenous infusion of insulin has been measured in normal individuals during hypoglycaemia and when hypoglycaemia was prevented by the concurrent infusion of glucose. When euglycaemia was maintained, mean (+/- S.D.) specific insulin binding following the 5 hour insulin infusion was unchanged (6.9 +/- 2.1 to 6.65 +/- 2.2% bound per 2.25 X 10(9) erythrocytes). In the presence of mild hypoglycaemia, mean (+/- SD) specific insulin binding rose from 6.6 +/- 2.3 to 7.6 +/- 2.5% bound per 2.25 X 10(9) erythrocytes (P less than 0.01), after 5 hours. This increase was due to increased receptor affinity. It was not correlated with the increase in the concentration of any individual counter-regulatory hormone. Initial insulin receptor binding correlated strongly with the subsequent decline in plasma glucose concentration (r = 0.9527; P less than 0.01). Thus, acute hyperinsulinaemia, when associated with hypoglycaemia, does not result in downregulation of insulin receptors on erythrocytes but rather results in increased receptor binding. Consequently, the insulin receptor may not play an active role in protecting the individual against acute hypoglycaemia.     

Intensified conventional insulin treatment and neuropsychological impairment.

OBJECTIVE--To assess whether intensified insulin treatment, with an increased frequency of hypoglycaemic episodes, leads to cognitive deterioration. DESIGN--Prospective randomised trial of intensified conventional treatment and standard treatment. SETTING--Outpatient clinic for patients with insulin dependent diabetes. SUBJECTS--96 patients with insulin dependent diabetes, high blood glucose concentrations, and non-proliferative retinopathy were randomised to intensified conventional treatment (n = 44) or standard treatment (n = 52). MAIN OUTCOME MEASURES--Glycated haemoglobin concentration (metabolic control); the number of hypoglycaemic episodes reported by patients at each visit; results of computerised neuropsychological tests performed at entry and after five years. RESULTS--Mean glycated haemoglobin concentration during the study was 7.2% (SE 0.1%) with intensified conventional treatment and 8.7 (0.1%) with standard treatment (p less than 0.001). During five years 34 (77%, 95% confidence interval 53% to 100%) of the patients given intensified treatment and 29 (56%, 36% to 75%) of the others had at least one episode of serious hypoglycaemia (p less than 0.05). The intensified conventional treatment group had a mean of 1.1 episodes of serious hypoglycaemia per patient per year compared with 0.4 episodes in the standard treatment group. Results of the neuropsychological tests were similar in the two groups after five years. CONCLUSIONS--Intensified conventional insulin treatment led to lower blood glucose concentrations and a higher frequency of hypoglycaemic episodes, but patients showed no signs of cognitive deterioration.     

U500 Regular Insulin use in Insulin-Resistant type 2 Diabetic Veteran Patients

ObjectiveTo evaluate the use of U500 regular insulin therapy in insulin-resistant patients with type 2 diabetes mellitus who were previously treated with high-dosage U100 insulin regimens.Methods:At a large Veterans Affairs medical center, a retrospective chart review was performed of all patients whose U100 insulin regimens were converted to U500 regular insulin regimens using a protocol to ensure patient safety. Patients were followed up for longer than 6 months. Data reviewed included total daily dosage of insulin before and after regimen conversion and changes in hemoglobin A1c, body weight, lipids, and episodes of severe hypoglycemia.ResultsFifty-three patients met inclusion criteria. Average hemoglobin A1c level on U100 insulin regimens was 9.1 ± 1.7%, which decreased to 8.1 ± 1.3% (P < .001) after an average of 20 months (range, 6-52 months) on U500 insulin. The total daily insulin dosage at study end was not significantly greater on U500 (415 ± 166 units/day) than on U100 insulin (391 ± 120 units/day) (P = .34). Body weight did not change significantly (134 ± 29 kg vs 136 ± 30 kg, P = .18). There was a 20-mg/dL decrease in total cholesterol (P = .014). Triglyceride values decreased by 97 mg/dL (P = .005). Eight episodes of severe hypoglycemia were documented in patients treated with U500 insulin, but this was similar to the incidence in these same patients while treated with U100 insulin.ConclusionWe conclude that U500 insulin can be safely and effectively used in insulin-resistant patients with type 2 diabetes followed up at a large Veterans Affairs medical center using a protocol that ensures patients are thoroughly educated and carefully monitored. (Endocr Pract. 2012;18:34-38)     

Type B Insulin Resistance Syndrome Associated with Systemic Lupus Erythematosus

ObjectiveTo document a case of type B insulin resistance syndrome associated with systemic lupus erythematosus.MethodsWe present the clinical course of a female patient with type B insulin resistance syndrome, from the onset, diagnosis, and empiric treatment until remission of her disease.ResultsA 40-year-old African American woman with systemic lupus erythematosus presented with a relatively acute onset of severe hyperglycemia in January 2004. Her hyperglycemia was resistant to treatment with high doses of insulin (up to an equivalent dose of regular insulin of 4,500 units daily). The diagnosis of type B insulin resistance syndrome was confirmed after her insulin receptor antibody was found to be strongly positive. The patient’s hemoglobin A1c level improved substantially after she had been treated with azathioprine for 3 months. By November 2004, she was able to discontinue insulin therapy. Repeated insulin receptor antibody testing in February 2005 revealed that her insulin receptor antibody had become negative. The patient’s fasting glucose level became normal, and only occasional mild postprandial hyperglycemic episodes have been noted.ConclusionImmunosuppressive therapy with azathioprine seems to be responsible for our patient’s remission of type B insulin resistance, although the possibility of the occurrence of a spontaneous remission cannot be completely excluded. (Endocr Pract. 2007;13:51-55)     

Adenosine effects on glucose oxidation of adipocytes isolated from streptozotocin-diabetic rats.

Streptozotocin-induced diabetes did not impair the response of adipocytes to adenosine effects in glucose oxidation. The greatest effect of adenosine in potentiating the action of insulin was in the physiological concentration range of insulin (10-100 mu units/ml). The desensitization of cells by diabetes to the effects of insulin is therefore probably not related to the response of cells to adenosine.     

Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats

We evaluated the effect of chronic exercise on insulin secretion in response to high-glucose by using a perifusion method with isolated pancreatic islets from normal rats. Male Wistar rats were assigned to one of two groups: a sedentary group and a trained group. Running exercise was carried out on a treadmill for one hour per day, five days per week, for six, nine, or 12 weeks. The chronic exercise significantly enhanced the insulin secretion ability of pancreatic islets in response to the high-glucose stimulation upon nine and 12 weeks of exercise. The insulin content in the pancreas and the weight of the pancreas did not change upon nine weeks of exercise. Potassium-stimulated insulin secretion was also increased in the islets isolated from rats that trained for nine weeks compared with that in sedentary rats, suggesting that insulin secretion events downstream of membrane depolarization are involved in targets of the exercise effect. These findings suggest that chronic exercise could be a useful strategy not only for the maintenance of peripheral insulin sensitivity but also for the promotion of islet function to secrete insulin in non-diabetics.     

Clinical Experience with U500 Insulin: Risks and Benefits

ObjectiveTo describe our clinical experience with U500 insulin in insulin-resistant patients, including change in glucose control, body weight, insulin dose, and hypoglycemic episodes.MethodsIn September 2010, we undertook a retrospective chart review of patients who had U500 insulin in their medication list in the preceding 2 years who were treated in the endocrinology section at Dartmouth Hitchcock Medical Center. Glycosylated hemoglobin (A1C), body weight, and insulin dosage were documented before U500 insulin introduction, after 6 months of U500 insulin use, and at the last clinic visit when the patient was still taking U500 insulin. Hypoglycemic episodes and number of daily injections were recorded.ResultsRecords of 53 patients were analyzed, one of the largest reports of U500 insulin use published to date. The mean A1C level decreased from 10.1% before U500 insulin was initiated to 9.1% after 6 months of U500 use to 8.6% at the last follow-up visit (mean follow-up was 36.6 ± 24 months). At the last charted visit, body weight increased by a mean of 6.8 kg and insulin dosage increased by a mean of 0.44 units/kg. We observed a significant increase in the number of nonsevere hypoglycemic episodes and a decrease in the number of daily injections.ConclusionPatients with uncontrolled, severely insulin-resistant diabetes can be satisfactorily treated with U500 insulin with the potential to improve glycemic control. An increase in body weight, insulin dosage, and the number of nonsevere hypoglycemic episodes was observed. (Endocr Pract. 2012;18:56-61)     

Qualitative abnormality of insulin secretion in a case with insulinoma.

We have presented here a case of atypical insulinoma. Despite the recurrent episodes of hypoglycemic symptoms, the plasma level of insulin has never been excessive at fasting or by regular provocative tests. Detailed examination had demonstrated qualitative abnormality of insulin secretion. Hyposuppressibility of insulin secretion by hypoglycemia, borderline diabetic curve of glucose tolerance test, blunted response ot insulin to glucagon and leucine were the principle characteristics of these abnormalities. After removal of adenoma, insulin response to glucose, glucagon and leucine was improved. Only secretion provoked a high level of insulin and this abnormal elevation was no longer seen after the removal of adenoma. A removed elevation was no longer seen after the removal of adenoma. A removed insulinoma contained 25 U of immunoreactive insulin per gram tissue, but was negative for aldehyde-fuchsin staining. On electromicroscopy only atypical beta-cell granules were seen.     

Bile salts promote the absorption of insulin from the rat colon

The absorption of insulin mixed with sodium deoxycholate (DOC) or sodium cholate from the rectal mucosa of diabetic and non-diabetic rats was measured by the effect on blood glucose levels. Blood sugar was lowere by 50% one hour after administration of 12 u soluble insulin mixed with 1–10 mg/ml DOC, or 2–20 mg/ml sodium cholate. There was a linear correlation between the reduction in blood glucose and the amount of insulin administered (1–64 units) when mixed with 5 mg/ml DOC. Radioimmuno-assay of plasma insulin showed an increase from 16.2 μu/ml to 3335 muuu/ml after rectal administration of 12 u soluble insulin. We conclude that insulin when mixed with bile salts can be absorbed by the intestine to reach the circulation in a biologically active form.     

A Prospective Trial of U500 Insulin Delivered by Omnipod in Patients With Type 2 Diabetes Mellitus and Severe Insulin Resistance

ObjectiveTo test the effectiveness and safety of U500 regular insulin delivered by continuous subcutaneous insulin infusion (CSII) via the Omnipod insulin delivery system in patients with uncontrolled type 2 diabetes mellitus and severe insulin resistance.MethodsIn this prospective, 1-year, proof-of-concept trial, patients with insulin-requiring type 2 diabetes who had a hemoglobin A1c level of 7.0% or higher and severe insulin resistance (average insulin requirement, 1.74 units of insulin per kilogram each day; range, 1.4 to 2.64 units of insulin per kilogram [average insulin dose, 196.4 units daily]) were identified at routine office visits at Mountain Diabetes and Endocrine Center in Asheville, North Carolina, between December 2007 and August 2008. All patients had been on intensive insulin therapy with or without oral agents for more than 3 months. All patients were switched from baseline failed therapy to U500 regular insulin by continuous subcutaneous insulin infusion via Omnipod. Effectiveness was assessed by hemoglobin A1c measurement and 72-hour continuous glucose monitoring at baseline and at weeks 13, 26, and, 52 and by treatment satisfaction assessed by the Insulin Delivery Rating System Questionnaire at baseline and at week 52 while on U500 via Omnipod.ResultsTwenty-one adults were enrolled (mean age, 54 years; mean duration of diabetes, 4 years; mean body mass index, 39.4 kg/m2; mean insulin requirement, 1.7 U/ kg per day; and mean hemoglobin A1c, 8.6%) whose previous treatment with U100 insulin regimens had failed. Twenty patients completed the study. Treatment with U500 insulin via Omnipod significantly reduced hemoglobin A1c by 1.23% (P < .001) and significantly increased the percentage of time spent in the blood glucose target range (70- 180 mg/dL) by 70.75% as assessed by continuous glucose monitoring (P < .001) without a significant increase in hypoglycemia. Patients were satisfied with treatment with U500 insulin via Omnipod, and 14 patients elected to remain on treatment at study completion.ConclusionsU500 insulin delivered subcutaneously continuously via Omnipod is a safe and effective method of insulin delivery in the very insulin-resistant type 2 diabetic population. (Endocr Pract. 2010;16:778-784)