Factitious hypoglycemia in insulin-treated diabetic patients

Factitious hypoglycemia is a factitious disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), referring to intentionally covertly induced hypoglycemia, with potentially severe consequences. Knowledge of factitious hypoglycemia relies on case reports, and evidence-based information and guidelines are lacking. Diagnosing factitious hypoglycemia in insulin-treated diabetic persons is therefore challenging and often requires a long and costly process. Moreover, the typical metrics proposed to differentiate insulin-induced factitious hypoglycemia from insulinoma (i.e., high insulin and low C-peptide versus high insulin and high C-peptide, respectively) are not always applicable, depending on whether the insulin quantification method can detect the insulin analog. When factitious hypoglycemia is suspected, an emerging trend from recent publications advocates a combination of two insulin quantification methods with different cross-reactivity for insulin analogs, early on in the diagnostic process.     

Blood glucose control and insulin secretion improved with combined therapy in type 2 diabetic patients with secondary failure to oral hypoglycaemic agents

The influence of combined therapy using insulin and oral hypoglycaemic agents on blood glucose control and on insulin secretion in Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents was evaluated. Type 2 diabetic patients (n = 180) (98 normal-weight, 82 over-weight), at least 3 years from diagnosis, and having poor blood glucose control on oral hypoglycaemic agents for at least 3 months (fasting plasma glucose greater than 10.0 mmol l-1) despite intensive efforts at improvement, were included in the study. A single daily insulin injection (human ultralente), at a dose of 0.22 +/- 0.07 U kg-1 d-1 in normal-weight and 0.33 +/- 0.10 U kg-1 d-1 in over-weight patients, was added to the previous dietary and drug treatment for 6 months. A progressive and significant (2p less than 0.001) reduction of the mean daily blood glucose was observed during the first 3 months of combined therapy (from 13.2 +/- 3.2 to 8.1 +/- 2.1 mmol l-1 in normal-weight and from 13.4 +/- 3.1 to 8.8 +/- 2.3 mmol l-1 in over-weight patients), with no further significant changes thereafter. A significant increase (2p less than 0.001) in the mean daily C-peptide concentration (from 0.50 +/- 0.30 to 0.71 +/- 0.29 nmol l-1 in normal-weight and from 0.78 +/- 0.36 to 1.00 +/- 0.41 nmol l-1 in over-weight patients) took place during combined therapy. No changes of body weight (+ 1.5 +/- 1.2 kg in normal-weight and + 1.0 +/- 1.0 kg in over-weight patients) were observed.     

Discrimination of type I from insulin-treated type II diabetic patients by C-peptide measurement

Summary Residual B-cell function was assessed in 61 type I and 17 type II insulin-treated diabetics by measuring plasma C-peptide concentration before and after i.v. injection of 1 mg glucagon to evaluate a possible difference in response to the test in the two groups. Fasting and poststimulatory C-peptide levels were significantly higher in type II diabetics than in type I (0.45±0.25vs 0.12±0.10 nmol/l for basal IRCP, 0.39±0.19vs 0.06±0.11 nmol/l for ΔIRCP, p<0.0001), but there was some overlap in individual values. Twenty-one percent of type 1 and 29% of type II diabtics had values in the overlap area. These percentages were reduced to 6% and 12%, respectively when only long-term (duration of diabetes more than five years) type I diabetics were considered. These data indicate that a glucagon test is useful to discriminate most type I diabetics from insulin-treated type II diabetics.     

Free insulin concentrations in immediately extracted plasma samples and their relationships to clinical and metabolic parameters in insulin-treated diabetic patients

Summary The relationships between free insulin and various clinical and metabolic parameters in insulin-treated diabetic patients are still not clear, possibly because of the technical difficulties in measuring free insulin. Recently, it has been demonstrated that in the presence of insulin antibodies only immediate centrifugation of blood and extraction of insulin antibodies provide an accurate evaluation ofin vivo free insulin concentrations. In this study we evaluated the relationships between free and bound insulin levels, insulin antibodies, metabolic control and insulin requirement in 38 insulin-treated diabetic patients, in whom plasma free insulin was assayed in immediately processed samples. The main findings of our study are as follows. Free insulin concentrations ranged from 2.5 to 54 μU/ml; no difference was found between males and females; the unbound hormone level was inversely correlated to fasting plasma glucose (p<0.01) and HbA_lc (p<0.02); a positive correlation was shown between free insulin and daily insulin dose; finally, free insulin concentrations were not correlated with insulin antibody binding. This study was supported by theConsiglio Nazionale delle Ricerche (C.N.R.), Special Project ‘Diabetes’, Grant n ^o 82.02254.56, and byMinistero della Pubblica Istruzione.     

The role of ranitidine infusion on glucose,insulin and C-peptide serum levels induced by oral glucose tolerance test in healthy subjects

Summary In 9 healthy subjects we evaluated the effect of a constant ranitidine infusion (100 mg) on glucose (mg/dl), insulin (μU/ml) and C-peptide (ng/ml) serum levels promoted by oral glucose tolerance test (75 g). Ranitidine significantly increased the area under concentration/time curves for glucose and insulin but not that of C-peptide. Our data indicate that ranitidine does not affect pancreatic insulin release nor peripheral glucose utilization and are consistent with the hypothesis that ranitidine influences the hepatic clearance of glucose and insulin both of which undergo high first-pass liver extraction.     

Red cell sorbitol levels during hyper and hypoglycaemic clamp studies in insulin-dependent diabetic patients

The red cell sorbitol concentration has been suggested as a measure of polyol pathway activity. Red cell sorbitol levels were higher in 53 patients having insulin-dependent diabetes mellitus (IDDM) than in 16 control subjects. Six patients having IDDM underwent hyperglycaemic 'clamp' studies; the red cell sorbitol level returned to the normal range when the blood glucose was clamped at 5 mmol/l for 1 h and rapidly increased when it was clamped at 15 and 25 mmol/l for a further hour at each level. Seven patients with IDDM were rendered hypoglycaemic; red cell sorbitol levels rapidly fell to a level less than, but not significantly different from normal. The results of these studies suggest that in IDDM red cell sorbitol levels are a reflection of prevailing blood glucose concentration and do not indicate long-term sorbitol accumulation in other tissues.     

C-peptide as a key risk factor for non-alcoholic fatty liver disease in the United States population

AIM To determine whether fasting C-peptide is an independent predictor for non-alcoholic fatty liver disease(NAFLD) in United States population.METHODS Using the National Health and Nutrition Examination Survey(NHANES) 1988-1994, NAFLD participants aged 20 or greater without any other liver diseases were included in this study. Excessive alcohol intake is defined as 2 drinks per day for males and 1 drink per day for females. C-peptide and 27 other factors known to be associated with NAFLD(e.g., age, gender, body mass index, waist circumference, race/ethnicity, liver chemistries, and other diabetes tests) were tested in both univariate and multivariate level using logistic regression with a P-value 0.05.RESULTS Of 18825 participants aged ≥ 20, 3235 participants(n = 3235) met inclusion criteria. There were 23 factors associated with NAFLD by univariate analysis. 9 factors, ranked by the highest change in pseudo R2, were found to be significant predictors of NAFLD in multivariate model: waist circumference, fasting C-peptide, natural log of alanine aminotransferase(ALT), total protein, beingMexican American, natural log of glycated hemoglobin, triglyceride level, being non-Hispanic white, and ferritin level. CONCLUSION Together with waist circumference and ALT, fasting C-peptide is among three most important predictors of NAFLD in United States population in the NHANES data set. Further study is needed to validate the clinical utility of fasting C-peptide in diagnosis or monitoring insulin resistance in NAFLD patients.     

Plasma C-peptide and serum insulin antibodies in diabetic patients receiving pancreatic transplants

Summary Plasma C-peptide and serum insulin antibody levels were determined in 5 diabetic patients undergoing vascularized pancreatic transplantation. The grafts functioned well at first and exogenous insulin could be withdrawn, but one to 7 weeks later the grafts were rejected. After the transplantation there was an increase in the fasting plasma C-peptide level, and B-cell stimulation with glucose or glucagon evoked a C-peptide response. Healing of ischaemic damage was reflected in an increase in the C-peptide level. During graft rejection the C-peptide level fell. Measurement of plasma C-peptide levels provides a direct index of the B-cell function of the pancreatic graft. After transplantation the insulin antibody level fell exponentially, with an apparent half life of 10–11 days, whereas the level of total IgG was variable. The results indicate that formation of insulin antibodies ceases immediately on removal of the immunogenic stimulus, that is, on withdrawal of xenogeneic insulin.     

Serum free C-peptide response to oral glucose loading as a parameter for the monitoring of pancreatic B-cell function in diabetic patients

As a parameter for evaluating pancreatic B-cell function, the accuracy of measuring serum free C-peptide immunoreactivity (CPR) was compared with that of measuring plasma immunoreactive insulin (IRI) and urine CPR in diabetic patients during a 100 g oral glucose tolerance test. In 25 non-obese patients receiving oral hypoglycemic agent or diet treatment alone, a positive correlation between the sum of serum free CPR (sigma serum free CPR) and the sum of plasma IRI (sigma plasma IRI) was noted (r = 0.68, P less than 0.001). However, the sum of blood glucose values was found to be negatively correlated to sigma free CPR (r = -0.56, P less than 0.0025), but not to sigma plasma IRI (r = -0.25, NS). In 23 patients receiving diet, oral hypoglycemic agent or insulin treatment, a positive correlation between sigma serum free CPR and urine CPR was noted (r = 0.75, P less than 0.001). However, no significant correlation was found when only insulin-treated patients were investigated (r = 0.37, NS, n = 17). In addition, patients with insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus were better differentiated by measuring sigma serum free CPR than urine CPR. Thus, we concluded that the measurement of serum free CPR during OGTT provides an extremely valuable method for monitoring pancreatic B-cell function in diabetic patients, whether they are receiving insulin treatment or not.     

Urine C-peptide in relation to the degree of insulin dependence in diabetic patients

Urine C-peptide per 24 h urine (UCPR) was assayed and correlated with the degree of insulin dependence in 324 diabetic patients. The UCPR and UCPR/weight were 74.7 +/- 26.3 micrograms/day and 1.27 +/- 0.36 micrograms/day, kg in healthy subjects, and these values were similar in diet- and sulfonylurea-treated patients. Insulin-dependent diabetics (IDDM) with history of ketosis or ketoacidosis and/or unstable plasma glucose, and patients refractory to sulfonylureas had lower UCPR values (8.5 +/- 6.6 and 22.3 +/- 14.6 micrograms/day) than the other insulin-treated patients (45.4 +/- 30.7 micrograms/day). In more than 90% of diet- and sulfonylurea-treated patients, UCPR exceeded 30 micrograms/day and UCPR/wt. exceeded 0.6 micrograms/day, kg. UCPR was less than 20 micrograms/day and UCPR/wt. less than 0.4 microgram/day,kg in more than 90% of IDDM patients, and less than 40 micrograms/day and 0.8 microgram/day,kg respectively in 80% of sulfonylurea-refractory patients. IDDM patients with more than 20 U/day of insulin doses had lower UCPR values. Longer duration of diabetes was associated with lower UCPR in IDDM patients. The results indicate that UCPR more than 30 micrograms/day or UCPR/wt. more than 0.6 micrograms/day,kg suggest non-insulin dependence, and UCPR less than 20 micrograms/day or UCPR/wt. less than 0.4 micrograms/day,kg suggest insulin dependence. Assay of UCPR provides a simple, non-invasive test for evaluating the degree of insulin dependence in diabetic patients.     

Glycaemic variability and hypoglycaemia are associated with C-peptide levels in insulin-treated type 2 diabetes

AimThe aim of the study was to evaluate the association between C-peptide levels, glycaemic variability and hypoglycaemia in patients with insulin-treated type 2 diabetes (T2D).MethodsA total of 98 patients with T2D treated with basal-bolus insulin were enrolled in a cross-sectional study. Glycaemic variability and hypoglycaemia were assessed from continuous glucose monitoring (CGM) data recorded over 6 days: Glycemic variability was assessed by calculating the mean coefficient of variation (CV), while hypoglycemia was defined as sensor glucose levels ≤ 3.9 mmol/L or < 3.0 mmol/L. Fasting C-peptide and fasting glucose were measured on day 1.ResultsLow levels of fasting C-peptide correlated with higher CV (r = −0.53, P < 0.0001). In a multivariate regression model with HbA_1c, body mass index, diabetes duration and total daily insulin dose, only C-peptide was significantly associated with CV. Patients with ≥ 1 episode of hypoglycaemia had significantly lower median C-peptide levels than patients without hypoglycaemia (274 (136–620) pmol/L vs. 675 (445–1013) pmol/L, respectively; P = 0.0004). Also, 17 patients clinically diagnosed with T2D had detectable glutamic acid decarboxylase (GAD) antibodies (≥ 5 U/mL). These GAD-positive patients had significantly lower fasting C-peptide, higher CV and greater frequency of hypoglycaemia than GAD-negative patients.ConclusionIn patients with insulin-treated T2D, low levels of C-peptide are associated with greater glycaemic variability and higher risk of hypoglycaemia, suggesting that C-peptide levels should be taken into consideration when optimizing insulin treatment and assessing hypoglycaemia risk.     

Randomized controlled multicentre evaluation of an education programme for insulin-treated diabetic patients: effects on metabolic control, quality of life, and costs of therapy.

A multicentre controlled randomized education study was performed to evaluate an education programme for insulin-treated diabetic patients. The main objective of the education programme, which took place on an out-patient basis, was to improve the level of self-care of the participants. Fifteen randomly recruited hospitals (558 patients) were equally divided into three groups: two experimental groups who completed the programme under the guidance of a health care professional or a fellow patient, and a control group. Patients in the experimental group were evaluated four times and those in the control group twice, with an intervening period of 6 to 7 months. The effect of the programme on metabolic control, quality of life, and costs of therapy was assessed. No significant effect of education of any one of these variables could be found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Near visual acuity: a simple measure of practical significance in insulin-treated diabetic patients.

The value of measuring near visual acuity as a predictor of loss of independence in administering insulin and monitoring blood or urine glucose has been assessed in 110 insulin-treated diabetic patients. Near visual acuity was simple to measure in the clinic setting, and correlated well with 6 m acuity. Fourteen patients depended on an assistant either to draw up the correct dose of insulin (n = 12), inject the insulin (n = 7) or to monitor blood or urine glucose (n = 12). Of these 14 patients only one, who was demented, had near visual acuity better than N.12. Two other patients had near visual acuity N.12 or worse and yet were independent of help. One had severe visual impairment and used a pen-injector and a meter with speech synthesizer, and the other had near visual acuity of N.12. Impairment of near visual acuity to N.12 or worse is associated with loss of independence in insulin-treated diabetes. Measurement of near visual acuity could be useful in predicting independence of insulin-treated patients.     

A simple clinical approach to discriminate between “true” and “pseudo” secondary failure to oral hypoglycaemic agents

To discriminate between true secondary failure (TF) and pseudo-secondary failure (PF) to oral hypoglycaemic agents, we studied 34 non-obese non-insulin-dependent diabetic patients who were being treated with these drugs. Nine were in good control (GC) with oral treatment, while 25 showed apparent SF. During a controlled hospital diet, fasting blood glucose remained persistently high in 15 of these patients (TF), while in the other 10 patients it clearly improved (PF). Fasting plasma glucose (FPG) and HbA_1c were higher and body mass index (BMI) was lower in TF patients than in PF patients (P<0.01). C-peptide concentrations differed significantly among the three groups both in the fasting state (TF 0.25±0.02 nmol/l, PF 0.70±0.03 nmol/l, GC 0.74±0.03 nmol/l;P<0.0001) and 6 min after glucagon injection (TF 0.50±0.04 nmol/l, PF 1.02±0.06 nmol/l, GC 1.14±0.07 nmol/l;P<0.0001). C-peptide and plasma insulin curves obtained after a standard mixed meal also showed significant differences (P<0.001). In particular, there was a statistically significant difference between GC and PF versus TF (P<0.05), while there was no statistical difference between PF and GC. We conclude that some patients with apparent SF can improve their metabolic control if they strictly adhere to a correct diet (PF); a single measurement of basal C-peptide concentration or examination of the C-peptide and insulin responses to a meal are useful indicators for distinguishing patients with PF from those with TF to oral hypoglycaemic agents. Lower BMI and higher fasting plasma glucose and HbA_1c are additional and simple indicators of TF.     

Insulin,C-peptide and glucagon levels during ogtt in hepatic cirrhosis and in patients with prehepatic block

Summary In order to investigate pancreatic B-cell function in hepatic cirrhosis and to elucidate the role of porto-caval shunt-circulation in the development of hyperinsulinism and hyperglucagonemia in cirrhotic patients, blood glucose, plasma insulin and glucagon, and serum C-peptide concentrations were measured during OGTT in 11 control and 16 cirrhotic subjects as well as in 7 patients with prehepatic block secondary to thrombosis of the portal vein. Insulin and glucagon levels were significantly higher in the cirrhotic than in the control group (for insulin: p<0.01, <0.001, <0.01 and <0.05 at 0, 60, 90 and 120 min, respectively; for glucagon: p<0.01, <0.01, and <0.05 at 0, 30 and 60 min, respectively). Serum C-peptide levels were, however, similar in the two groups with the exception of the 30-min value, which was significantly lower in the cirrhotic group (p<0.05). Plasma insulin and glucagon concentrations in patients with prehepatic block were similar to those of the controls but significantly lower than the values found in cirrhotic patients (for insulin: p<0.05 and <0.01 at 30 and 60 min, respectively; for glucagon: p<0.01, <0.01 and <0.05 at 0, 30, 60 min, respectively). Serum C-peptide levels of these patients were not significantly different either from the control values or from those obtained in the cirrhotic group. Accordingly, pancreatic B-cell secretion is not increased in hepatic cirrhosis. Hence, the hyperinsulinism is due to decreased hepatic degradation of the hormone. Decreased degradation of both insulin and glucagon should be attributed mainly to parenchymal liver damage, rather than porto-systemic shunting.     

Circadian variation of serum glucose,C-peptide immunoreactivity and free insulin in normal and insulin-treated diabetic pregnant subjects

Summary To examine differences among pregnant diabetic and nondiabetic subjects, serum glucose, and immunoreactivity of C-peptide, free and total insulin were measured at hourly intervals during a 24-h third trimester metabolic ward evaluation. Six normals, three mild, and four juvenile-onset type diabetics were studied. Diets were identical for all subjects. Mild diabetics differed from juvenile diabetics by having significant residual pancreatic B-cell function, as measured by C-peptide immunoreactivity. Short and intermediate acting insulins given once or twice daily to diabetics maintained serum glucose levels within the normal range throughout the 24 h. Despite wide variation in serum total insulin levels, peripheral free insulin concentrations in well-controlled diabetics fell within a relatively narrow range that was higher than in controls. Infants of the diabetic subjects were comparable to the offspring of the control women.This study was supported through funds provided by the Bureau of Medicine and Surgery, Navy Department, for CIP 4-48-364, and USPHS grants AM-13941 and AM-17046 (University of Chicago Diabetes Endocrinology Center). The group in Chicago also was supported by a gift from the Bertha and Henry Brownstein Foundation.These data were presented in part before the Endocrine Society, New York, New York, 18 June 1975.The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the naval service at large.On leave of absence from Kyoto University Medical School, Kyoto, Japan.     

Clinical application of the 24-H urinary C-peptide excretion rate and its relationship to metabolic control in diabetics

Summary In this study, we evaluated in normal subjects, insulin-dependent (IDD) and non-insulin-dependent (NIDD) diabetics, the diurnal urinary C-peptide excretion rate (CPR-U) and its relationship to serum C-peptide concentration and glucose:C-peptide molar ratio, and to the common parameters of metabolic control. The CPR-U (and CPR-U/g creatinine) were significantly lower in IDD and higher in NIDD compared to control subjects. Moreover, a good and significant correlation with serum C-peptide concentrations and the glucose:C-peptide ratio in diabetic subjects as well as in controls and diabetics considered together was found. A slight but significant correlation was present in diabetic subjects between CPR-U and body mass index (r=0.45), 24-h glycosuria (r=−0.36), HbA1 levels (r=−0.31), post-prandial glucose concentrations (r=−0.26) and per cent glucose variation after each meal (r=−0.34). No differences were found in CPR-U and the degree of metabolic control between obese and non-obese NIDD. In conclusion, CPR-U may be a useful and simple method of defining the secretory activity of the B-cell. Metabolic control in diabetics is slightly correlated to the degree of B-cell function as evaluated by the diurnal excretion rate of C-peptide in urine. Part of this paper was presented at the National Meeting of the Italian Diabetes Association, Bari, May 27–29, 1982.     

C-peptide concentrations in patients with type 2 diabetes treated with insulin

AimsTo determine beta cell reserves of patients with type 2 diabetes who are treated with insulin by using fasting C-peptide concentrations and to investigate the clinical features related to C-peptide concentrations.Materials and methodsPatients with type 2 diabetes, who were using insulin as monotherapy or in combination therapy, were divided into three groups; those with an insufficient beta cell reserve (C-peptide: <0.5 ng/mL), borderline reserve (C-peptide: 0.5–2 ng/mL) and sufficient reserve (C-peptide:> 2 ng/mL).ResultsIn the 249 patients (mean age, 61.77 ± 9.34 years; 40.6% male), the mean duration of diabetes was 13.9 ± 8.43 years. The mean HbA1c concentrations, fasting glucose and C-peptide concentrations were 8.88 ± 1.87%, 184.29 ± 77.88 mg/dL and 1.95 ± 1.37 ng/mL, respectively. Fifty-seven percent of patients (n = 142) had a borderline beta cell reserve and 37% (n = 92) had high C-peptide concentrations. Only 6% of patients (n = 15) had an insufficient beta cell reserve. C-peptide levels were positively correlated with waist circumference (r: 0.282; p = 0.001), hip circumference (r: 0.251; p = 0.001), body mass index (r: 0.279; p = 0.001), fasting glucose concentrations (r: 0.309; p = 0.001) and triglyceride concentrations (r: 0.358; p = 0.001).ConclusionIn this study, almost all patients with type 2 diabetes using insulin were found to have sufficient or borderline beta cell reserves and insulin resistance-related parameters were prominent in those with adequate beta cell reserve.Clinical trials noNCT04005261     

Comparison of oral glucose loading and intravenous glucagon injection as stimuli to C-peptide secretion in normal men

In 10 healthy men, we have compared the respective effects of an intravenous injection of glucagon (1 mg) and an oral glucose load (75 G) in eliciting the release of C-peptide and insulin from the pancreas. Serum C-peptide and insulin concentrations increased respectively to median values of 190% and 500% at 6 minutes after glucagon injection, and 344% and 794% at 30 minutes and 268% and 278% at 60 minutes following glucose ingestion. The oral glucose load was as effective as glucagon injection in testing beta cell function and was free from the unpleasant side effects (nausea, vomiting, syncope) commonly associated with glucagon. We conclude that oral glucose loading is probably the test of choice to elicit C-peptide release when screening populations of normal subjects for adequacy of beta cell function.     

Consequences of systemic venous drainage and denervation of heterotopic pancreatic transplants for insulin/C-peptide profiles in the basal state and after oral glucose

Plasma glucose, immunoreactive insulin and C-peptide concentrations were compared in nine pancreas-kidney-transplanted patients (systemic venous drainage) and in ten non-diabetic kidney-transplanted patients with similar kidney function. In the basal state, C-peptide (insulin secretion) was similar, but immunoreactive insulin was higher and glucose concentrations were slightly, but significantly lower in pancreas-transplanted patients. After 50 g oral glucose, the plasma glucose and IR-insulin profiles were similar in both groups. The circumvention of first-pass hepatic insulin extraction (decreased endogenous insulin clearance) was compensated for by a significant reduction in insulin secretion (C-peptide; p=0.036). In conclusion, hyperinsulinaemia in pancreas-transplanted patients with systemic venous drainage is significant only in the basal state. Insulin delivered into the portal and peripheral circulation, when leading to similar insulin profiles, maintains comparable degrees of glucose tolerance.