Comment on Nathan DM Buse JB Davidson MB et al

Authors: T Takamura A Shimizu H Ando S Kaneko

Publish Date: 2006/11/23

Volume: 50, Issue: 1, Pages: 229-230

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Abstract

Glucoseresponsive insulin secretion is frequently impaired prior to the onset of type 2 diabetes 1 In addition considering the reduced pancreatic beta cell mass in patients with type 2 diabetes 2 defects in insulin secretion appear heterogeneous in this patient group In some patients only postprandial insulin secretion appears impaired whilst in others basal insulin secretion is also affected However postprandial insulin secretion is impaired in almost all patients with type 2 diabetesIn the recently published consensus statement from the American Diabetes Association 3 and the European Association for the Study of Diabetes 4 concerning the initiation and adjustment of therapy for managing hyperglycaemia in type 2 diabetes initial insulin therapy is aimed at increasing basal insulin supply with intermediate or longacting insulins Such a regimen cannot completely mimic a physiological pattern of insulin secretion Consequently postprandial glycaemic control tends to be inadequate and a risk exists of fasting hypoglycaemia Furthermore the postprandial hyperglycaemia observed in patients with earlystage or mild type 2 diabetes increased the risk of microangiopathy or arteriosclerosis in two largescale clinical studies of type 2 diabetes the United Kingdom Prospective Diabetes Study 5 and the DECODE study 6 It has also been suggested that therapy focused on lowering postprandial glucose rather than fasting glucose may be superior for lowering HbA1c 7 and glucose variability spike 8 Insulin preparations have been developed to provide insulin replacement that more closely reflects physiological insulin secretion the introduction of rapidacting insulin analogues and longacting soluble insulin analogues has been a further step in this direction Rapidacting insulin analogues have been particularly effective at targeting postprandial hyperglycaemia 8 They can therefore effectively reduce postprandial plasma glucose even if administered immediately before a meal and also minimise the risk of hypoglycaemia prior to the next meal 8The exact contribution of postprandial and fasting glucose increments to overall hyperglycaemia remains controversial Monnier et al reported that postprandial glucose excursion contributes up to ∼70 of the glucose load in patients with diabetes whose HbA1c levels are 73 whereas the contribution of fasting hyperglycaemia increases gradually as diabetes worsens 9 However even in patients whose glycaemic control is poor studies have demonstrated that treatment targeting postprandial hyperglycaemia which improves glucoseresponsive insulin secretion in patients with glucose desensitisation improves both postprandial and also morning fasting plasma glucose FPG in such patients 10 11 12We hypothesised that mealtime dosing with rapidacting insulin analogues strictly controls postprandial and daytime plasma glucose levels and thereby improves glucose desensitisation and glucoseresponsive insulin secretion To test these hypotheses we recently evaluated the effect of a mealtime rapidacting insulin analogue on the minimum early morning FPG levels nadir FPG in 40 Japanese patients with type 2 diabetes whose existing antidiabetic medication was discontinued 12 Approximately half 525 of the patients achieved a nadir FPG of 67 mmol/l with mealtime dosing of a rapidacting insulin analogue alone No basal insulin replacement was needed in these patients Patients on the other hand whose FPG levels remained high even after postprandial hyperglycaemia improved were presumed to have defects in basal insulin secretion 12 To further confirm our finding we prospectively followed 160 patients with type 2 diabetes treated with mealtime dosing of a rapidacting insulin analogue After 1 year of treatment at our outpatient clinic about 60 of these patients were able to continue this therapy successfully FPG was 64 ± 16 mmol/l and HbA1c was 65 ± 11 compared with FPG of 60 ± 12 mmol/l and HbA1c of 69 ± 11 in the patients who required additional basal insulin replacement Takamura et al unpublished observation This suggests that basal insulin secretion was maintained in these patients and only prandial insulin secretion was impaired For such patients glycaemic control achieved with sulfonylureas which continuously promote insulin secretion or with a longacting insulin may increase the risk of fasting hypoglycaemia It may also contribute to obesity as a result of differentiation or hyperplasia of adipocytes during episodes of hyperinsulinaemia Such patients may benefit instead from treatment with rapidacting insulin analogue preparations which more closely mimic physiological insulin secretion These formulations may reduce the risk of hypoglycaemia by achieving a better balance between glucose and insulin levels and also minimise increases in obesity which might otherwise result from persistent hyperinsulinaemia during periods of fasting or after mealsBased on these findings we propose mealtime dosing with a rapidacting insulin analogue as an initial insulin regimen for patients with type 2 diabetes This regimen may be superior in lowering postprandial glucose excursion and the glucose spike which are cardiovascular risk factors The regimen may also help reduce the risk of hypoglycaemia and obesity associated with insulin therapy Because not only postprandial but also FPG can be modestly reduced by this regimen the requirement for basal insulin replacement should be considered only in patients who do not achieve good FPG levels thereafter

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