Euglycaemic glucose clamp: what it can and cannot do, and how to do it.

The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the "gold standard" for the assessment of pharmacodynamic (PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose (BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic-euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic-euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under-reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies.

Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance.

AIMS/HYPOTHESIS: Type 2 diabetes has been associated with upper gastrointestinal motility dysfunction, but the relationship with diabetes duration and glucose control is less well understood. Gastric emptying, oesophageal motility and gastrointestinal symptoms were examined in volunteers with diabetes, prediabetes (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]) and normal glucose tolerance (NGT). METHODS: The study included 41 patients with type 2 diabetes, 17 individuals with IFG/IGT and 31 individuals with NGT. A gastric emptying breath test and high-resolution oesophageal manometry were performed. Gastrointestinal symptoms were assessed using questionnaires. RESULTS: Gastric emptying was delayed in individuals with IFG/IGT (p < 0.05) but was normal in the diabetic group. Amongst the diabetic patients, gastric emptying rate was fastest in those with longer diabetes duration and the highest HbA1c levels (p < 0.001). Oesophageal motility variables were similar between the groups. However, the lower oesophagus resting pressure was reduced in patients with longer diabetes duration (p = 0.01). Abdominal pain/discomfort was more frequent amongst patients with diabetes (p = 0.04) but was unrelated to gastric emptying. Significant associations between various oesophageal motility variables and gastrointestinal symptoms were observed. CONCLUSIONS/INTERPRETATION: Gastric emptying and oesophageal motility are not generally altered in patients with type 2 diabetes. In more advanced disease stages, however, gastric emptying and oesophageal motility may be disturbed, probably as a consequence of autonomic neuropathy. Delayed gastric emptying in IFG/IGT individuals might be secondary to acute hyperglycaemia. Determination of gastric emptying and oesophageal manometry should be considered for the diagnostic workup of patients with diabetes and gastrointestinal symptoms.

Variability of skin autofluorescence measurement over 6 and 12 weeks and the influence of benfotiamine treatment.

BACKGROUND: Measurements of skin autofluorescence (SAF) allow for a simple and noninvasive quantification of tissue advanced glycation end-products (AGEs), a marker linked to the risk of diabetes complications. The aim of this study was to test the repeatability of SAF over 6 and 12 weeks and to test whether benfotiamine, a thiamine prodrug suggested to reduce AGEs formation under hyperglycemic conditions, is able to attenuate SAF when administered over 6 weeks. PATIENTS AND METHODS: In a double-blind, placebo-controlled, randomized, crossover study, 22 patients with type 2 diabetes mellitus (T2DM) received 900 mg/day benfotiamine or placebo for 6 weeks (washout period of 6 weeks between). At the beginning and at the end of each treatment period, SAF was assessed in the fasting state, as well as 2, 4, and 6 h following a mixed test meal. RESULTS: The respective intra-individual and inter-individual variability of fasting SAF was 6.9% and 24.5% within 6 weeks and 10.9% and 23.1% within 12 weeks. The respective variability calculated for triplicate comparisons was 9.9% and 27.7%. A short-term therapy with benfotiamine did not influence SAF significantly, nor did we find a significant postprandial SAF increase. CONCLUSIONS: In patients with T2DM, repeated, timely spaced SAF measurements have an intra-subject variability of below 11%. Using these data, sample sizes were calculated for interventional studies aiming at reducing SAF. Benfotiamine treatment for 6 weeks did not significantly influence SAF; for this, a longer-term therapy is probably needed.

Parameters affecting postprandial blood glucose: effects of blood glucose measurement errors.

BACKGROUND: The Diabetes Error Test Model (DETM) has been developed to characterize the clinical relevance of the large and varying margins of error of parameters affecting postprandial blood glucose (BG) levels, which increase the risk for hypo- or hyperglycemia. METHODS: The DETM is based on a treatment concept aimed at normoglycemia after meals. The model includes as parameters (a) preprandial BG measurement by patient self-monitoring (SMBG), (b) patient estimate of carbohydrate amounts (CARB-P) in food, (c) effect of CARB-P on maximum BG increase, (d) effect of insulin on maximum BG decrease, and (e) insulin dosage. Covering the relevant range of preprandial BG (30-330 mg/dl), the DETM simulates the maximum effect of these parameters and their margins of error on postprandial BG values. RESULTS: According to the DETM, a SMBG error of +20% results in normoglycemia (BG range: 60-160 mg/dl) as the postprandial outcome if preprandial BG values are in the range of 30-130 or 260-330 mg/dl, but can unexpectedly result in hypoglycemia if preprandial BG values are between 131 and 259 mg/dl. If the SMBG error of +20% is combined, e.g., with an error of CARB-P estimate in the food of +20%, hypoglycemia as the postprandial outcome is worsened. If one combines the effects of errors of more than two parameters, even with errors that are so small that they have no clinically relevant dysglycemic effect on postprandial BG per se (e.g., +/-6%), this can result in postprandial hypo- or hyperglycemic values. CONCLUSION: The DETM simulates the effects of errors of parameters affecting postprandial BG within the clinically relevant BG range. The DETM offers the opportunity to evaluate the clinical relevance of these errors and their contribution to the increased risk of meal-related excessive glucose excursions during intensified insulin therapy.