One hundred years ago: the dawning of the insulin era.

The dawn of the insulin era can be placed in 1921, when Banting and Best started their experiments which led, a year later, to the successful treatment of diabetes. They were preceded by the discoveries of the pancreatic cause of diabetes by Minkowski and von Mering in 1889 and of the islets by Paul Langerhans in 1869. The achievement of the first targeted treatment in medical history was a landmark of medical progress. However, it was accompanied by a mixture of human greatness and misery. Genius and recklessness, ambition and deception, camaraderie and rivalry, selflessness and pursuit of glory went along with superficial search of the existing literature, poor planning, faulty interpretation of results, failure to reproduce them, and misquoting of reports from other laboratories. Then as now, such faults surface whenever human nature aims to push forward the boundaries of knowledge and pose a real challenge in today's world, as the scientific method strives to keep healthy in the face of growing anti-scientific feelings.

Development and pharmacist-mediated use of tools for monitoring atypical antipsychotic-induced side effects related to blood glucose levels.

PURPOSE: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor-intensive and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels. METHODS: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings. RESULTS: The management tool reduced the pharmacists' effort in collecting information on patients' prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects. CONCLUSIONS: The results suggested that regardless of pharmacists' experience or skill, the introduction of this tool enables centralization of side effect monitoring and can contribute to proper drug use.

Evaluation of 1,5-anhydro-d-glucitol in clinical and forensic urine samples.

Because of the lack of characteristic morphological findings post mortem diagnosis of diabetes mellitus and identification of diabetic coma can be complicated. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for renal reabsorption. Therefore low serum concentrations of 1,5-AG, reflect hyperglycemic excursions over the prior 1-2 weeks in diabetic patients. Next to clinical applications determination of 1,5-AG can also be used in forensic analysis. To investigate the elimination of 1,5-AG, a liquid chromatographic-mass spectrometric method for the determination of 1,5-AG and creatinine in urine was developed and validated according to international guidelines. To evaluate ante mortem concentrations of 1,5-AG spot urine samples of 30 healthy subjects, 46 type 1 and 46 type 2 diabetic patients were analyzed. 1,5-AG urine concentrations of diabetic patients were significantly (p<0.001) lower (mean: 1.54µg/ml, n=92) compared to concentrations of healthy subjects (mean: 4.76µg/ml, n=30) which led to the idea that 1,5-AG urine concentrations post mortem might help in the interpretation of a diabetic coma post mortem. Urine of 47 deceased non-diabetics, 37 deceased diabetic and 9 cases of diabetic coma were measured. Comparison of blood and urine 1,5-AG concentrations in clinic samples (linear, R2=0.13) and forensic samples (linear, R2=0.02) showed no correlation. Urinary levels of 1,5-AG in deceased diabetic (mean 6.9µg/ml) and in non-diabetic patients (mean 6.3µg/ml) did not show a significant difference (p=0.752). However, urinary 1,5-AG concentrations in deceased due to diabetic coma (mean: 1.7µg/ml) were significantly lower than in non-diabetic (mean: 6.3µg/ml, p=0.039) and lower than in diabetic cases (mean: 4.7µg/ml, p=0.058). The determination of a reliable cut-off for the differentiation of diabetic to diabetic coma cases was not possible. Normalization of urinary 1,5-AG concentrations with the respective creatinine concentrations did not show any gain of information. In clinical (serum) and forensic blood samples a significant difference between all groups could be detected (p<0.05). Comparison of blood and urine 1,5-AG concentrations in clinical samples (linear, R2=0.13) and forensic samples (linear, R2=0.02) showed no correlation.

Glycated hemoglobin A1c as a risk factor for severe hypoglycemia in pediatric type 1 diabetes.

OBJECTIVE: To assess the risk of severe hypoglycemia related to glycated hemoglobin A1c (HbA1c) levels in a population-based cohort of pediatric type 1 diabetes patients during two time periods since 1995. METHODS: The association between HbA1c levels and severe hypoglycemia (defined as requiring assistance from another person) or hypoglycemic coma (loss of consciousness or seizures) was analyzed by multivariable regression analysis in children and adolescents with type 1 diabetes from the DPV Diabetes Prospective Follow-up in Germany and Austria in 1995-2003 (n = 15 221 patients) and 2004-2012 (n = 22 318 patients). RESULTS: Mean adjusted rates of severe hypoglycemia and hypoglycemic coma decreased from 19.18 [95% confidence interval (CI), 17.95-20.48] and 4.36 (3.93-4.83) per 100 patient-years in 1995-2003 to 15.01 (14.18-15.88) and 2.15 (1.94-2.39) in 2004-2012, respectively (p < 0.001). From the first to the second period, the relative risk (RR) for severe hypoglycemia and hypoglycemic coma per 1% lower HbA1c decreased from 1.22 (1.15-1.30) to 1.06 (1.01-1.12) and from 1.27 (1.15-1.40) to 1.04 (0.94-1.16), respectively. Risk of severe hypoglycemia and coma declined most in patients with HbA1c levels of 6-6.9% (RR 0.70 and 0.43, respectively) and with HbA1c of 7-7.9% (RR 0.63 and 0.38, respectively). Mean HbA1c levels fell from 8.4% in 1995-2003 to 8.2% in 2004-2012, while the use of insulin pumps, short- and long-acting insulin analogs, and glucose monitoring increased (p < 0.001). CONCLUSIONS: In contrast to 1995-2003, low HbA1c has become a minor risk factor for severe hypoglycemia and coma in pediatric patients with type 1 diabetes in the 2004-2012 period.

Detection of diabetic metabolism disorders post-mortem--forensic case reports on cause of death hyperglycaemia.

Diabetic coma is the most severe form of hyperglycaemic metabolic disorders. The post-mortem diagnosis of this disorder of glucose metabolism can be difficult and vague due to a lack of characteristic morphological findings. Six death cases caused by diabetic coma are described with special focus on biochemical (and histological) findings. The possible glycaemia markers glucose, lactate, HbA1c, fructosamine, anhydroglucitol, and ketone bodies were measured and the usefulness of these parameters is evaluated and discussed. Estimations of glucose concentrations in vitreous humour or cerebrospinal fluid and of ketone bodies in blood or other matrices are obligatory while measurements of HbA1c, fructosamine, or anhydroglucitol can only provide additional information on the long-term adjustment of diabetes in the deceased. Lactate concentrations (addition of glucose and lactate levels to form the sum formula of Traub) do not give more information than the glucose concentration itself and can be therefore omitted.

Clinical and forensic examinations of glycaemic marker methylglyoxal by means of high performance liquid chromatography-tandem mass spectrometry.

The postmortem determination of hyperglycaemic coma is quite difficult because of the lack of morphological findings and the difficult interpretation of biochemical parameters. Methylglyoxal (MG) is a reactive oxoaldehyde, which is mainly derived from glycolysis. An electrospray ionisation liquid chromatography-tandem mass spectrometric procedure for the determination of methylglyoxal in human serum and postmortem blood was developed. It involves protein precipitation with perchloric acid and a derivatisation step with 2,3-diaminonaphthalene. The assay was validated according to international guidelines. Serum samples from diabetics obtained at a diabetes clinic and from non-diabetics were used to assess data about reference concentrations in human serum. The assay showed linearity within the physiological concentrations in serum (5-500 ng/ml). Intraday imprecision at three concentrations was 10.3, 9.2 and 8.3 %, and interday imprecision was 15.3, 14.2 and 9.4 %; the limit of detection was 1.3 ng/ml, and limit of quantification, 3.2 ng/ml. One hundred and eighteen clinical (100 diabetics, 18 non-diabetics) and 98 forensic samples (84 non-diabetics, 14 in a status of hyperglycaemic coma) were measured. During life, diabetics showed significantly (p < 0.001) higher serum concentrations of MG than non-diabetics. After death, concentrations of MG increased significantly (p < 0.001). However, there was no correlation between the sum formula of Traub in vitreous humour and MG femoral blood concentrations (R = 0.237). This indicates that MG concentrations in the deceased cannot distinguish deaths due to a hyperglycaemic coma from other causes of death.

Clinical and forensic examinations of glycemic marker 1,5-anhydroglucitol by means of high performance liquid chromatography tandem mass spectrometry.

Postmortem diagnosis of diabetes and a diabetic coma can be difficult because of the lack of characteristic morphological findings. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for reabsorption in the kidneys. Therefore, diabetics with a permanent hyperglycemia show significantly lower serum concentrations of 1,5-AG than non-diabetics. A liquid chromatography-mass spectrometric method for the determination of 1,5-AG in serum and postmortem blood was developed and validated according to international guidelines. Linearity was given between 1 µg/ml and 50 µg/ml. Recovery rates ranged between 70.8% and 89.8%, the limit of quantification of the procedure was 0.20 µg/ml, limit of quantification was 0.55 µg/ml. Serum of 199 diabetics and 116 non-diabetics and femoral blood of 31 diabetic and 27 non-diabetic deceased was measured. Average concentrations were significantly (p<0.001) higher in non-diabetics compared to diabetics ante and postmortem. Seven of the diabetics may have died because of a hyperglycemic coma indicated by a sum formula of Traub>450 mg/dl. 1,5-AG average concentrations in these deceased were not significantly different to diabetics which did not die because of a diabetic coma. Concentrations of 1,5-AG give a hint for not well controlled diabetes antemortem and postmortem and can be assumed as an additional and alternative information postmortem to the measurement of HbA1c or fructosamine.

[Insulin pump therapy: indications and risks - Case 7/2010]. / Insulinpumpentherapie: Indikationen und Risiken - Fall 7/2010.

UNLABELLED: HISTORY, ADMISSION FINDINGS AND TREATMENT: In a 35-year-old pregnant woman (pat. 1) with type 1 diabetes, insulin pump therapy was initiated because of very fluctuating blood glucose levels with severe hypoglycaemias and worsening hypoglycaemia unawareness during pregnancy. In a 45-year-old female (pat. 2) with type 1 diabetes, severe hypoglycemia with loss of consciousness occurred because of dysfunction of the insulin pump and subsequent several-fold application of bolus insulin. After intravenous administration of 40% glucose solution the patient recovered soon and was admitted to hospital for further treatment. COURSE: With CSII blood glucose levels were in patient 1 more stable and HbA (1c) remained within the normal range. The pregnancy proceeded without further complications and the patient gave birth to a healthy boy on time. In patient 2, insulin pump treatment was reinititated after a temporarily change to an intensified conventional insulin regimen and an insulin pump therapy education update. CONCLUSION: The main advantage of an insulin pump therapy is the higher flexibility regarding the basal insulin rate, in particular in patients with highly fluctuating insulin demand during the day and/or hypoglycaemia unawareness. As a disadvantage can be seen the higher costs, especially as superiority of insulin pump therapy compared to intensified conventional treatment could not be shown for all patients.

[Hypoglycemia despite hyperglycemia. Is a cerebral glucose deficiency possible even with raised blood sugar levels?]. / Hypoglykämie trotz Hyperglykämie. Ist eine zerebrale Minderversorgung mit Glukose auch bei erhöhtem Blutzuckerspiegel möglich?

Hypoglycemia represents the most frequent endocrinologic emergency situation in prehospital patient care. As the patients are usually unconscious on arrival of emergency medical personnel, often the only way to establish a diagnosis is by determination of the blood glucose concentration. However, even normoglycemic or hyperglycemic levels cannot definitively exclude the diagnosis of a previous hypoglycemia as the cause of the acute cerebral deficiency. Therefore, and especially in the case of insulin-dependent diabetes mellitus, a differential diagnosis should be considered. We report a case of emergency treatment of a hypoglycemic episode in a female patient with prolonged neuroglycopenia together with cerebrovascular dementia and Alzheimer's disease.

[Intracranial hypertension in severe diabetic ketoacidosis with coma. Two cases]. / Hypertension intracrânienne au cours de l'acidocétose diabétique grave avec coma. Deux observations.

We observed two cases of severe diabetic ketoacidosis with coma and shock. In one case, coma was present at admission and in the second occurred within 15 hours. In both cases, intracranial hypertension was confirmed with an extradural captor. These findings are in agreement with observations of brain oedema in diabetic ketoacidosis with coma. Clinical data suggest that brain oedema may occur after a latency period but that clinical expression is much more rare, perhaps favoured by treatment (excessive rehydratation, alkalinization, too sharp drop in blood glucose level). In our cases, despite major fluid infusion, shock persisted requiring norepinephrine. This shock could have been the expression of the severe ketoacidosis or have resulted from an underlying infection. In case of sudden onset coma, a regularly encountered manifestation of brain oedema, respiratory assistance and mannitol infusion must be instituted rapidly. With this type of management, it should be possible to improve the severe prognosis of brain oedema in diabetic ketoacidosis.

Opposite changes in serum sodium and potassium in patients in diabetic coma.

We studied the changes in serum sodium (Na) and potassium (K) levels in seventeen patients in diabetic ketoacidosis and nine patients in non-ketotic hyperosmolar coma, who had marked hyperglycemia (707.4 +/- 75.6 mg/dl, mean +/- SEM) and dehydration. The disorder characterized two types of alteration. The one group was hyponatremia with hyperkalemia in 17 patients in diabetic ketoacidosis (132.9 +/- 2.0 and 5.7 +/- 0.2 mEq/l), and 4 patients in non-ketotic hyperosmolar coma (125.8 +/- 4.3 and 5.2 +/- 0.5 mEq/l). The other was hypernatremia (162.5 +/- 1.8 mEq/l) with hypokalemia (3.4 +/- 0.2 mEq/l) in 5 patients in non-ketotic hyperosmolar coma. Intensive therapy with insulin and fluid administration improved the diabetic hyperglycemia and associated abnormalities. The vectors showing the normalization of serum Na and K levels was in quite opposite directions between the patients with hyponatremia with hyperkalemia and those with hypernatremia with hypokalemia. The amounts of loss of circulatory blood volume exceeded 20% in three groups of patients, a loss greater in the hypernatremic patients than in the hyponatremic ones. These results indicate that serious body water depletion produces hypernatremia instead of hyponatremia in patients in diabetic coma. The disorder may be caused by the altered distribution of electrolytes between the intra- and extra-cellular spaces.

[The reactivity of the mesenteric arterioles to adrenaline in metabolic coma]. / Reaktivnost' arteriol bryzheiki k adrenalinu pri metabolicheskoi kome.

The reactivity of mesoappendix arterioles to applicated epinephrine application was investigated in 2 models of metabolic coma, hypoglycemic and acetonemic. Hypoglycemic coma (HC) was induced by insulin injection (20 IE/kg) i. m. to rats fasting for 18 hours. Acetonemic coma (AC) was induced by i. v. acetone injection (5.5 mmol). The sensitivity of arterioles to applicated epinephrine did not change in HC and increased twofold in AC vs. the control values (p < 0.01). The reaction of arterioles to injection of double threshold dose of epinephrine in HC developed sooner and the degree of vasoconstriction was 41% higher than in controls. In AC the reaction developed two times sooner and the degree of arterioles constriction was 1.5 times higher vs. the control (p < 0.01).

Diabetic ketoacidosis--a study of 33 episodes.

Twenty-six patients presenting with 33 episodes of Diabetic Ketoacidosis (DKA) and managed on a protocol oriented system were analysed. Diabetes mellitus was newly diagnosed at presentation in 18% of the 33 episodes. The presenting symptoms were polyuria and polydipsia (58%), nausea and vomiting (52%), change in sensorium (24%), hyperventilation (24%), and abdominal pain (18%). The main clinical findings at admission were dehydration (97%), acidotic respiration (67%), coma and confusion (61%), a clinically detectable source of sepsis (49%), fever (33%) and hypotension (9%). Blood sugar levels at admission ranged between 351 mg/dl and 1200 mg/dl (mean = 633 mg/dl). The mean serum potassium at diagnosis was 5.1 mmol/l and the mean calculated serum osmolality was 320 mOsm/kg. The mean serum osmolality was higher in those with disturbed conscious level. Infections, particularly those of the urogenital tract, were the main precipitating cause for the DKA. Only 12 of the 19 patients with sepsis had fever. Eight of the episodes were attributed to patients' non-compliance with insulin. Four patients died during the 33 hospitalisations, giving a mortality rate of 10%. Death occurred despite glucose control and stabilisation of the ketoacidotic state and was due to uncontrolled septicaemia. The mean duration of hospitalisation was 11 days. The ketoacidosis state was reversed after a mean duration of 9.5 hours, with an average soluble insulin requirement per patient of 52.4 units.

[The postmortem assessment of glycemia by the levels of blood glucose and glycosylated hemoglobin]. / Posmertnaia otsenka glikemii po urovniu gliukozy i glikozilirovannogo gemoglobina krovi.

The results of cadaveric blood investigation in order to diagnose glycemia directly before death are presented. During the analysis of the whole blood glucose concentration was determined by glucose oxidase method as well as percentage of glycosylated Hb was determined by colorimetric method by colour reaction with thyobarbituric acid. On the basis of the results obtained conclusion was made about failure in use of glucose concentration for medicolegal purposes. Estimation of glycosylated Hb content was suggested as criterion for glycemia detection.

[Diagnostic value of detection of blood levels of lactate, pyruvate and 2,3-diphosphoglycerate in children with diabetes mellitus]. / Diagnosticheskoe znachenie opredeleniia urovnia laktata, piruvata i 2,3-difosfoglitserata v krovi pri sakharnom diabete u detei.

Measurements were made of lactate, pyruvate and 2,3-diphosphoglycerate in 69 children admitted to the hospital in a state of diabetic ketoacidosis of different intensity. Depending on the intensity of metabolic abnormalities, the content of lactate and pyruvate was found to be increased, whereas that of 2,3-diphosphoglycerate to be lowered. Measurements of the content of lactate and the lactate/pyruvate ratio enables carrying out differential diagnosis between the ketoacidotic and lactacidotic varieties of diabetic coma.

Glucose metabolism in a patient with insulinoma complicated by hyperosmolar non-ketotic state.

A case of a patient with organic hyperinsulinism complicated by the development of hyperosmolar state is described. The hyperosmolar state was induced by vomiting and dehydration during an acute urinary tract infection. Impairment of glucose metabolism was confirmed by the finding of reduced tissue sensitivity to insulin during a euglycaemic clamp.

Prompt recovery of plasma arginine vasopressin in diabetic coma after intravenous infusion of a small dose of insulin and a large amount of fluid.

We studied the changes in plasma arginine vasopressin in 5 patients with diabetic ketoacidosis and one patient with non-ketotic hyperosmolar coma who had marked hyperglycemia (36.6 +/- 4.6 mmol/l, mean +/- SEM) and dehydration. Plasma osmolality (Posm) was 342.2 +/- 11.4 mOsm/kg H2O, and hematocrit, serum protein, and blood urea nitrogen were also elevated at hospitalization. Circulating blood volume was decreased by approximately 21% as compared with that on day 7. Plasma AVP level was increased to 8.5 +/- 1.6 pmol/l at hospitalization. When hyperglycemia was improved by iv infusion of a small dose of insulin plus fluid administration, plasma AVP level promptly decreased to 2.4 +/- 0.4 pmol/l within six hours. When plasma AVP level had normalized, Posm was still as high as 305 mOsm/kg H2O, but the loss of circulating blood volume was only 4.2% of the control state. Plasma AVP level was positively correlated with change in hematocrit (plasma AVP = 3.58 + 0.45.hematocrit, r = 0.468, p less than 0.01), serum protein (r = 0.487, p less than 0.01), Posm (r = 0.388, p less than 0.01), and blood glucose (r = 0.582, p less than 0.01). Plasma AVP level was negatively correlated with the change in circulating blood volume (plasma AVP = 3.6 - 0.14.change in circulating blood volume, r = -0.469, p less than 0.01). These results indicate that both non-osmotic and osmotic stimuli are involved in the mechanism for AVP release in patients with diabetic coma, and that the non-osmotic control of AVP may contribute to circulating homeostasis, protecting against severe blood volume depletion in diabetic patients suffering from hyperglycemia and dehydration.