Endogenous Insulin Secretory Capacity Research Articles

Practice guideline: Statement regarding treatment for suspected slowly progressive type 1 diabetes (SPIDDM; probable) cases (English version).

Insulin treatment should be introduced in patients with slowly progressive type 1 diabetes (SPIDDM; definite), according to the revised diagnostic criteria of SPIDDM (2023). In contrast, SPIDDM (probable) patients are in a non-insulin-dependent state; therefore, a more flexible treatment can be considered, although sulfonylurea agents should be avoided. Insulin treatment has been shown to maintain endogenous insulin secretion capacity in SPIDDM (probable); however, this does not mean that all SPIDDM (probable) patients should use insulin from the early phase. Dipeptidyl peptidase-4 inhibitors and biguanides might be the treatment of choice for SPIDDM (probable), but no evidence exists for other hypoglycemic agents. In any case, careful monitoring of the endogenous insulin secretion capacity should be carried out, and if a decrease in insulin secretion capacity is suspected, a change in treatment should be considered to prevent progression to an insulin-dependent state.

C-peptide index at 2 h post-meal is a useful predictor of endogenous insulin secretory capacity and withdrawal from insulin therapy in subjects with type 2 diabetes.

To evaluate the correlation between C-peptide index (CPI) at 2 h post-meal and endogenous insulin secretory capacity and to develop clinical models to predict the possibility of withdrawal from insulin therapy in patients with type 2 diabetes. This was a single-centre retrospective study of patients with type 2 diabetes admitted to our hospital. Patients were divided into a withdrawal group (n = 72) and a non-withdrawal group (n = 75) based on whether they were able to withdraw from insulin therapy at discharge, and the correlation between CPI at 2 h after meal and diabetes-related parameters was evaluated. In addition, we created two clinical models to predict the possibility of withdrawal from insulin therapy using machine learning. The glycated haemoglobin values of the study participants were87.8 ± 22.6 mmol/mo. The CPI at 2 h post-meal was 1.93 ± 1.28 in the non-withdrawal group and 2.97 ± 2.07 in the withdrawal group (p < 0.001). CPI at 2 h post-meal was an independent predictor of withdrawal from insulin therapy. In addition, CPI at 2 h post-meal was a better predictor than fasting CPI. Six factors associated with insulin therapy withdrawal (age, duration of diabetes, creatinine, alanine aminotransferase, insulin therapy until hospitalization, and CPI at 2 h post-meal) were used to generate two clinical models by machine learning. The accuracy of the generated clinical models ranged from 78.3% to 82.6%. The CPI at 2 h post-meal is a clinically useful measure of endogenous insulin secretory capacity under non-fasting conditions.

THU367 Hyperosmolar Hyperglycemic State In A Middle-old Male With Primary Hyperparathyroidism

Abstract Disclosure: D.M. Dimayuga: None. M.C. Isidro: None. A 79-year-old male was brought to our hospital for drowsiness. He had low-grade fever with associated cough and anorexia 1 week prior. He had a previous history of hypertension and primary hyperparathyroidism (PHPT) maintained on cinacalcet. He did not have a history of diabetes and a family history of diabetes, and his HbA1c was 5.4% three months before. On admission, the results of his physical examination and vital signs were as follows: height, 152cm; weight, 56.0 kg; BMI, 24.2 kg/m2; temperature, 36.5C; heart rate, 85 beats/min; SpO2, 98% (on room air); respiratory rate, 22 breaths/min; and blood pressure, 115/60 mm Hg. His blood glucose level was 966 mg/dL, HbA1c 13.4%, and serum osmolality 324 mOsm/kg. Serum ketones were 15 mg/dL and blood gas analysis was normal. He was diagnosed with hyperglycemic hyperosmolar state (HHS) and infusion of insulin and saline was subsequently initiated. With clinical suspicion of chronic pancreatitis given the patient’s history of PHPT, serum lipase was checked, 105 U/L (NV: 12-53 U/L). Ionized calcium was 1.36 mmol/L. On CT scan of abdomen, there was no evidence of duct dilatation and calcification, and instead, “features of diffuse fatty atrophy of the pancreas” were seen. His endogenous insulin secretory capacity was sufficient (serum C-peptide: 2.76 ng/mL, NV: 0.78-5.19 ng/mL). Eventually, the patient’s level of consciousness improved and glycemic control was achieved. Soon after, insulin was shifted to basal-bolus regimen. On the 7th day of hospitalization, patient was discharged with minimal insulin requirements. Two weeks later, on follow up, his blood glucose levels were found to be stable. It was not clear whether our patient had new-onset autoimmune or type 2 diabetes. Although autoimmune diabetes generally occurs when about 90% of the pancreatic beta cells have been destroyed, the patient could have been in the honeymoon period wherein beta cell activity was transiently regained after commencement of insulin therapy. Our plan is to monitor his C-peptide titers and test his insulin antibodies. Evidence suggests that PHPT may cause insulin resistance and glucose intolerance. The rise in free intracellular calcium may reduce glucose transport in insulin-stimulated glucose transporters, increasing the need for insulin. This could be the case in our patient hence we diagnosed him with type 2 diabetes. To the best of our knowledge, this is the first case demonstrating the co-occurrence of HHS and PHPT. Presentation: Thursday, June 15, 2023

Glucagon Test Is a Useful Predictor of Withdrawal From Insulin Therapy in Subjects With Type 2 Diabetes Mellitus.

There are many tests for evaluating endogenous insulin secretory capacity. However, there are only a limited number of studies that have examined in detail in clinical practice which method most accurately reflects the ability to secrete endogenous insulin especially in hyperglycemic state. The purpose of this study was to find the endogenous insulin secretory capacity and a possible predictor of insulin withdrawal in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia. In the endogenous insulin secretory test during hospitalization, CPR, CPR index, and ΔCPR after glucagon loading were all significantly higher in the insulin withdrawal group. On the other hand, there were no difference in fasting CPR index, HOMA-β, SUIT, and 24-hour urinary CPR excretion between the two groups. In the glucagon test of the insulin withdrawal group, the cutoff value of ΔCPR was 1.0 ng/mL, the withdrawal rate of ΔCPR of 1.0 ng/mL or more was 69.2%, and the withdrawal rate of less than 1.0 ng/mL was 25.0%. In conclusion, it is likely that glucagon test is the most powerful tool for predicting the possibility of insulin withdrawal as well as for evaluating endogenous insulin secretory capacity in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia.

Serum c-peptide level in newly diagnosed Bangladeshi adults with type 2 diabetes mellitus

C-peptide is produced in equimolar amounts to insulin and is the best measure of endogenous insulin secretion. This cross-sectional study was conducted in a tertiary hospital of Bangladesh from January 2016 to December 2017 to assess fasting serum c-peptide as a marker of the endogenous insulin secretory capacity in newly diagnosed subjects with type 2 diabetes mellitus (T2DM). 60 newly diagnosed T2DM subjects were investigated along with 30 age-sex matched healthy controls. Fasting c-peptide was significantly higher in T2DM subjects than controls (8.97±5.96 vs. 1.69±0.66 ng/ml). None of the T2DM subjects had subnormal c-peptide, 19 (32%) had normal c-peptide, and 41 (68%) of them had elevated c-peptide levels. Higher fasting plasma glucose (FPG), plasma glucose 2-hours after 75gm oral glucose tolerance test (PG 2H-OGTT) and HbA1c levels were observed in T2DM subjects with elevated c-peptide in comparison to T2DM subjects having normal c-peptide. In T2DM subjects, c-peptide showed significant positive correlations with body mass index (BMI), FPG, PG 2H-OGTT, and HbA1c. This study found higher levels of fasting c-peptide in newly diagnosed T2DM in comparison to nondiabetic controls. None of the T2DM subjects had a subnormal c-peptide level.

Complete loss of insulin secretion capacity in type 1A diabetes patients during long-term follow up.

Aim/IntroductionPatients with type 1 diabetes are classified into three subtypes in Japan: acute onset, fulminant and slowly progressive. Acute‐onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese patients with long‐standing type 1A diabetes is unclear. The aim of the present study was to clarify the course of endogenous insulin secretion during long‐term follow up and the factors associated with residual insulin secretion in patients with acute‐onset type 1 diabetes (autoimmune).Materials and MethodsWe retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute‐onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C‐peptide levels and the results of glucagon stimulation test in 71 patients.ResultsIn the first year of disease, the child‐ and adolescent‐onset patients had significantly more in residual insulin secretion than the adult‐onset patients (34 patients in total). C‐peptide levels declined more rapidly in patients whose age of onset was ≤18 years than in patients whose age of onset was ≥19 years. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at >15 years after onset (61 patients in total).ConclusionsMost patients with acute‐onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset might affect the course of insulin secretion.

Chronic insulin infusion induces reversible glucose intolerance in lean rats yet ameliorates glucose intolerance in obese rats

BackgroundAlthough insulin resistance (IR) is a key factor in the pathogenesis of type 2 diabetes (T2D), the precise role of insulin in the development of IR remains unclear. Therefore, we investigated whether chronic basal insulin infusion is causative in the development of glucose intolerance. MethodsNormoglycemic lean rats surgically instrumented with i.v. catheters were infused with insulin (3mU/kg/min) or physiological saline for 6weeks. At infusion-end, plasma insulin levels along with glucose tolerance were assessed. ResultsSix weeks of insulin infusion induced glucose intolerance and impaired insulin response in healthy rats. Interestingly, the effects of chronic insulin infusion were completely normalized following 24h withdrawal of exogenous insulin and plasma insulin response to glucose challenge was enhanced, suggesting improved insulin secretory capacity. As a result of this finding, we assessed whether the effects of insulin therapy followed by a washout could ameliorate established glucose intolerance in obese rats. Obese rats were similarly instrumented and infused with insulin or physiological saline for 7days followed by 24h washout. Seven day-insulin therapy in obese rats significantly improved glucose tolerance, which was attributed to improved insulin secretory capacity and improved insulin signaling in liver and skeletal muscle. ConclusionModerate infusion of insulin alone is sufficient to cause glucose intolerance and impair endogenous insulin secretory capacity, whereas short-term, intensive insulin therapy followed by insulin removal effectively improves glucose tolerance, insulin response and peripheral insulin sensitivity in obese rats. General significanceNew insight into the link between insulin and glucose intolerance may optimize T2D management.

Pancreas-protective effect of rituximab for acute-onset type 1 diabetes in the honeymoon period: a case report.

SummaryA randomized controlled study of rituximab demonstrated that the drug protects pancreatic function in patients with acute-onset type 1 diabetes mellitus (AOT1DM). However, the mechanism of this protective effect is poorly understood. We examined the effects of rituximab in two patients with AOT1DM in the honeymoon period and the mechanism of these effects. Case 1 was a 40-year-old man and Case 2 was a 45-year-old man, both diagnosed with AOT1DM. Various tests indicated intact capacity for endogenous insulin secretion and that they were in the honeymoon phase of AOT1DM. Treatment with rituximab protected against pancreatic β-cell damage and maintained somewhat the endogenous insulin secretion. In Case 2, HbA1c level was maintained below 6.5% up to 24 months after treatment. However, in Case 1, the patient showed a gradual increase in HbA1c level starting around 9 months but fell at 12 months to >9.0% and required an insulin dose about twice greater than that of Case 2. High spleen tyrosine kinase (Syk) levels were recorded in the two patients before rituximab administration and after the treatment, the levels were further increased in Case 1, but decreased in Case 2. Both patients require continuous careful follow-up for glycemic control, insulin secretion capacity, and adverse reactions in the future. Although the clinical relevance of high Syk levels in AOT1DM patients remains unclear, the difference in the change in Syk level between the two patients may explain the different clinical courses.Learning pointsWe described the pancreas-protective effect of rituximab in two patients with acute-onset type 1 diabetes mellitus in the honeymoon period and investigated the possible mechanism of action.The present study demonstrated that treatment with rituximab maintained endogenous insulin secretion capacity for 2 years in the two patients.The phosphorylated-spleen tyrosine kinase (p-Syk) data suggest that the differences in HbA1c level and the required insulin dose between the two patients could be due to reactivation or nonreactivation of β-cells.

Association of morning fasting blood glucose variability with insulin antibodies and clinical factors in type 1 diabetes.

The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

Detection of C-Peptide in Urine as a Measure of Ongoing Beta Cell Function.

C-peptide is a protein secreted by the pancreatic beta cells in equimolar quantities with insulin, following the cleavage of proinsulin into insulin. Measurement of C-peptide is used as a surrogate marker of endogenous insulin secretory capacity. Assessing C-peptide levels can be useful in classifying the subtype of diabetes as well as assessing potential treatment choices in the management of diabetes.Standard measures of C-peptide involve blood samples collected either fasted or, most often, after a fixed stimulus (such as oral glucose, mixed meal, or IV glucagon). Despite the established clinical utility of blood C-peptide measurement, its widespread use is limited. In many instances this is due to perceived practical restrictions associated with sample collection.Urine C-peptide measurement is an attractive noninvasive alternative to blood measures of beta-cell function. Urine C-peptide creatinine ratio measured in a single post stimulated sample has been shown to be a robust, reproducible measure of endogenous C-peptide which is stable for three days at room temperature when collected in boric acid. Modern high sensitivity immunoassay technologies have facilitated measurement of C-peptide down to single picomolar concentrations.

Impacts of the Great East Japan Earthquake on diabetic patients.

Aims/IntroductionWe investigated impacts of the Great East Japan Earthquake on diabetic patients and characterized those with disaster-susceptible diabetes.Materials and MethodsWe enrolled 497 diabetic patients who had been followed at hospitals in devastated areas. We collected metabolic parameters prospectively, 1 and 3 months after the earthquake, and retrospectively for pre-earthquake time-points. Questionnaire surveys were carried out regarding earthquake-related damage and post-earthquake lifestyle alterations. Available data were analyzed to examine associations with post-earthquake glycosylated hemoglobin alterations.ResultsThe mean glycosylated hemoglobin level of the participants was not elevated at 1 month, and was significantly decreased at 3 months as compared with the pre-earthquake glycosylated hemoglobin. There were no significant differences in earthquake-related damage or lifestyle alterations between the improved and worsened glycemic control groups according to the data obtained from the questionnaire survey. As reported, fasting serum C-peptide levels were significantly lower in the worsened glycemic control group (P < 0.05). Notably, plasma noradrenaline levels were significantly higher in the worsened glycemic control group (P < 0.05). Furthermore, at 1 month after the earthquake, the plasma noradrenaline level was significantly higher in the low C-peptide group (fasting serum C-peptide <1.0 ng/mL) than in the high C-peptide group (fasting serum C-peptide ≥1.0 ng/mL), but this difference had disappeared by 3 months after the earthquake. These findings show that post-earthquake plasma noradrenaline levels were temporarily increased in the low C-peptide group.ConclusionsSympathetic nerve activation might be elicited more easily in subjects with lower endogenous insulin secretory capacity, and could be involved in the mechanism underlying post-earthquake worsening of glycemic control.

Efficacy of switching from premix analog insulin twice daily injection to insulin glargine once daily injection with sitagliptin

Forty-four patients with type 2 diabetes receiving twice daily injections of premix analog insulin were randomly allocated to Group A in which patients were switched to long-acting insulin glargine at 80 % of the insulin dose in the previous treatment regimen (23 patients), or Group B (21 patients) given 50 % of the previous dose, concurrently with the oral dipeptidyl-4 inhibitor sitagliptin. After patients had received their designated treatments without dose changes for 12 weeks, the insulin dose was adjusted and its usefulness was examined for 24 weeks. In the overall evaluation, significant improvement was observed in glycosylated hemoglobin (HbA1c), 1,5-anhydro-d-glucitol, fasting blood glucose, and low density lipoprotein cholesterol levels. The insulin glargine dose at 24 weeks was 65.0 % of the mixed formulation used in the previous treatment regimen. Although no significant change was observed in HbA1c levels in Group B during the study period, the level of 1,5-anhydro-d-glucitol increased significantly, while continuous glucose monitoring also showed improvement in postprandial hyperglycemia and nocturnal hypoglycemia. The change from baseline in HbA1c levels during the 24 weeks showed a significant negative correlation with C-peptide levels at the start of treatment, suggesting the usefulness of this regimen, particularly in patients maintaining endogenous insulin secretion capacity.

Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012)

Type 1 diabetes is a disease characterized by destruction of pancreatic β cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute-onset, or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute-onset type 1 diabetes mellitus. Among the patients who developed diabetic ketosis or ketoacidosis within 3 months after the onset of hyperglycemic symptoms and need insulin treatment continuously after the diagnosis of diabetes, patients with anti-islet autoantibodies are diagnosed with “acute-onset type 1 diabetes mellitus (autoimmune)”. On the other hand, those whose endogenous insulin secretion is exhausted [fasting serum C peptide immunoreactivity (CPR) < 0.6 ng/ml] without verifiable anti-islet autoantibodies are diagnosed simply with “acute-onset type 1 diabetes mellitus”. Patients should be reevaluated after certain periods in case their statuses of anti-islet autoantibodies and/or endogenous insulin secretory capacity is unknown.

Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus.

Type 1 diabetes is a disease characterized by destruction of pancreatic β-cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute-onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute-onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti-islet autoantibodies are diagnosed with 'acute-onset type 1 diabetes mellitus (autoimmune)'. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C-peptide immunoreactivity <0.6ng/mL) without verifiable anti-islet autoantibodies are diagnosed simply with 'acute-onset type 1 diabetes mellitus'. Patients should be reevaluated after certain periods in case their statuses of anti-islet autoantibodies and/or endogenous insulin secretory capacity are unknown.

Urinary C-peptide creatinine ratio to detect absolute insulin deficiency in type 2 diabetes

BackgroundNational Institute for Health and Clinical Excellence guidelines (CG87) recommend neutral protamine hagedorn (NPH) insulin for the provision of basal insulin in type 2 diabetes, but use of analogue insulin is as much as 40%. Where residual endogenous insulin secretory capacity is present there is no evidence that analogue insulins provide any additional benefit over human insulins, and they come at an expensive premium. Anecdotally, however, there is a reluctance to switch people back to NPH insulin, partly because of a perceived risk of pancreatic failure and potential ketosis. Urinary C-peptide creatinine ratio (UCPCR) has been validated as a method for evaluating residual endogenous insulin secretion in type 1 and type 2 diabetes, with a UCPCR of no more than 0·2 nmol/mmol suggestive of absolute insulin deficiency. We aimed to evaluate the prevalence of true insulin deficiency among patients with type 2 diabetes with UCPCR, and confirm findings with the gold standard mixed meal tolerance test (MMTT). Methods191 insulin-treated patients with a clinical diagnosis of type 2 diabetes (diagnosed at or after age 45 years and who did not start insulin within the first year of diagnosis) collected a 2-h post-prandial urine sample for UCPCR measurement. Nine patients from two subgroups (UCPCR ≤0·2 nmol/mmol and UCPCR >0·2) completed a standard MMTT. Findings11 (5·8%) of 191 patients had two consistent UCPCRs of less than or equal to 0·2 nmol/mmol. Nine were able to do the MMTT, of whom five were confirmed to have absolute insulin deficiency (stimulated serum c-peptide <0·2 nmol/L). Three of these five patients were glutamic acid decarboxylase antibody-negative. Nine of nine patients with UCPCR of more than 0·2 nmol/L had confirmed endogenous insulin secretion in their MMTT. Those with insulin deficiency had a shorter time to starting insulin (median 2·5 years [IQR 1·5–3·0] vs 6·0 [3·0–10·75], p=0·005) and lower body-mass index (25 kg/m2vs 29, p=0·04) but no other significant differences in clinical characteristics. InterpretationWe have demonstrated a very low prevalence of true pancreatic failure in this population of insulin-treated patients with type 2 diabetes. This requires further exploration by comparison of a population being treated with NPH insulin with one on analogue insulin, and then determining whether UCPCR could act as a clinical decision support tool to safely switch from analogue insulin to NPH insulin. FundingNational Institute for Health Research.

Effect of Sitagliptin in Type 1 or Type 2 Diabetic Patients with Absolute Insulin Deficiency: A 48 Weeks Observational Study

Aims: The aim of this study is to investigate the long-term efficacy of sitagliptin added to insulin in type 1 or type 2 diabetic patients with absolute insulin deficiency. Study Design: 48 weeks open-label, observational study. Place and Duration of Study: Department of Internal Medicine, Gyoda General Hospital, between June 2010 and December 2012. Methodology: Sitagliptin 25-100 mg/day was added to the ongoing insulin therapy in those without any detectable post-meal C-peptide levels. HbA1c and other parameters were followed for 48 weeks. Results: Effective reductions of HbA1c levels were already observed at 12 weeks and sustainable throughout the study period. However, 2 subjects had severe hypoglycemic evens. Post-meal C-peptide remained undetectable with all the subjects. Interestingly, significant increases of body weight were observed. Conclusion: Sitagliptin as an adjunct to insulin in patients with absolute insulin deficiency may be effective and sustainable for at least 48 weeks, allowing for less intense therapy. However, it should be noted that some patients may have severe Short Communication British Journal of Medicine & Medical Research, 3(4): 1910-1917, 2013 1911 hypoglycemic events. In spite of the significant glycemic effects of sitagliptin in the setting of this study, endogenous insulin secretory capacity remained absent, suggesting that the glucose lowering effect of this drug may be mediated through GLP-1 independent pathway as well.

The Treatment for Anti-insulin Antibody-mediated Immunological Insulin Resistance

Anti-insulin antibody is sometimes observed in diabetic patients treated by exogenous insulin. Anti-insulin antibody induces immunological insulin resistance and poor glycemic control. We previously reported a type 1 diabetic patient who showed severe insulin resistance due to insulin analog aspart-induced anti-insulin antibody [1]. He has been treated by using insulin aspart and insulin glargine. We treated him with the use of the newest insulin analog, insulin glulisine. This treatment significantly ameliorated his glycemic control and anti-insulin antibody 125I-binding rate, suggesting insulin glulisine as a possible treatment for other insulin analogmediated immunological insulin resistance [1]. We also reported a type 2 diabetic patient (patient A) who developed severe insulin resistance due to anti-insulin antibody after 2 years of use of insulin lispro and insulin detemir [2]. Switching to the treatment with insulin glulisine and insulin glargine improved glycemic control, however, anti-insulin antibody binding rate was still high. Finally, three pre-meal injections of insulin glulisine and discontinuation of insulin glargine (4 weeks) decreased anti-insulin antibody 125I-binding rate [2]. Basal insulin therapy using long-acting insulin analogs may be necessary for type 1 diabetic patient or type 2 diabetic patients who have no endogenous insulin secretion capacity. How can we treat these patients with long-acting insulin analogs-mediated anti-insulin antibody? Here, we will show the changes in HbA1c and anti-insulin antibody 125I-binding rate following the change in dose of insulin glulisine and insulin glargine in patient A (Fig. 1). Increased dose of insulin glulisine and 10 weeks-discontinuation of insulin glargine significantly decreased anti-insulin antibody 125I-binding rate, however, fasting blood glucose level (more than 200 mg/dl) and HbA1c level showed deterioration. After 10 weeks-discontinuation of insulin glargine, we re-started the use of low dose of insulin glargine. Fasting blood glucose and HbA1c levels were promptly decreased, and interestingly, anti-insulin antibody 125I-binding rate has been also continuously reduced. As the treatments for anti-insulin antibody-mediated insulin resistance or hypoglycemia, in addition to our reports [1, 2], cessation of insulin administration [3], glucocorticoids [4], the combination therapy using glucocorticoids, immunosuppressant and plasmapheresis [5, 6], and insulin lispro [7, 8] have been reported (Table 1). Increasing dose of insulin glulisine and the use of low dose of insulin glargine after the discontinuation of insulin glargine for a sufficient long period may be a new treatment for the anti-insulin antibodymediated immunological insulin resistance.

Comparative Study of Effectiveness of Multiple-Daily Injections of Insulin Versus Twice-Daily Injections of Biphasic Insulin in Patients with Type 2 Diabetes

To evaluate the efficacy of a multiple-daily injection regimen and a twice-daily injection regimen using biphasic insulin, we performed an observational study of 56 insulin-naïve patients with type 2 diabetes mellitus who began receiving insulin therapy while they were hospitalized. The subjects were divided into two groups: a multiple-daily injection group (n = 33), and a twice-daily injection group (n = 23). At baseline, the demographic and clinical characteristics were comparable between the two groups. The HbA1c levels were 10.0 +/- 1.6% and 9.5 +/- 2.2% (p = 0.36), respectively. At 12 weeks, the HbA1c levels decreased equally in the two groups (7.2 +/- 1.8% in the multiple-daily injection group and 7.3 +/- 1.6%, p = 0.80 in the twice-daily injection group). The baseline HbA1c, the duration of diabetes, and the endogenous insulin secretory capacity did not affect the change in HbA1c in either group. These results suggest that twice-daily insulin regimen using biphasic insulin is as effective and beneficial as multiple-daily injection regimen for the treatment in type 2 diabetic patients with very poor glycemic control and that in order to achieve the targeted glycemic goal, insulin therapy should be initiated at an early stage.

Evaluation of Endogenous Insulin Secretory Capacity by Using an Insulin Measurement Kit that has Low Cross-reactivity with Insulin Analogues

Evaluation of Endogenous Insulin Secretory Capacity by Using an Insulin Measurement Kit that has Low Cross-reactivity with Insulin Analogues

Feasibility and outcomes of insulin therapy in elderly patients with diabetes mellitus.

The use of insulin in elderly patients raises special considerations. Most people who develop diabetes mellitus late in life have type 2 diabetes mellitus, in which there is some residual endogenous insulin secretion. This pancreatic insulin secretion, when present, stabilises their metabolic status. However, some elderly people lose virtually all their endogenous insulin secretory capacity over time, or may even have type 1 (autoimmune) diabetes mellitus with no endogenous insulin. Generally, older patients with diabetes mellitus can be managed for years, often decades, with nutritional therapy and oral agents. More options exist now than did previously. In addition to a variety of sulfonylureas, there is metformin, troglitazone, and/or alpha-glucosidase inhibitors, that are viable options to be used before turning to insulin. The goals of insulin therapy in the elderly must be considered. When hyperglycaemia causes symptoms (polyuria, polydypsia and bodyweight loss) blood glucose levels are generally >200 mg/dl, and insulin is needed if maximal doses of oral agents have been used. Insulin is also indicated when hyperglycaemia puts patients at risk of hyperosmolar states, for example, when blood glucose is >300 mg/dl during a normal day. Clinical judgement dictates whether to use insulin to control glycaemia in the attempt to avoid long term complications such as neuropathy, retinopathy or nephropathy. In people with relatively short life expectancy, major comorbities and no sign of diabetic complications, the risk may be small. On the other hand, in patients for whom neuropathy, in particular, is a major risk, controlling glycaemia (with insulin if necessary) does reduce that risk. Most patients with type 2 diabetes mellitus can be managed with relatively simple insulin regimens thanks to their endogenous insulin secretion. A single bedtime dose of neutral protamine Hagedorn (NPH) insulin, with or without continuation of daytime oral agents, may control fasting blood glucose. A pre-mix combination of NPH and Regular insulin such as 70/30 or 50/50 may be used pre-meal. More customised, 'intensive' insulin regimens are needed when the glycaemia is unstable. Hypoglycaemia is clearly the most significant risk of insulin therapy. If mild and easily treated, it is of no real concern. On the other hand, nocturnal hypoglycaemia, and, in particular, hypoglycaemia unawareness, are clear signs that the insulin regimen should be modified. In summary, insulin therapy may be necessary, and can be used effectively, in elderly patients. However, risk:benefit considerations must be taken into account when deciding which patients to treat with insulin and what insulin regimen to use.