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Review: The importance of effective early phase insulin secretion

Stefano Del Prato, Roberto Miccoli and Giuseppe Penno British Journal of Diabetes & Vascular Disease 2005 5: 198 DOI: 10.1177/14746514050050040401 The online version of this article can be found at: http://dvd.sagepub.com/content/5/4/198

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The importance of effective early phase insulin secretion

STEFANO DEL PRATO, ROBERTO MICCOLI, GIUSEPPE PENNO
Abstract
selective loss of early phase insulin secretion is readily apparent when beta-cell function is assessed with the hyperglycaemic clamp technique. In response to square-waved hyperglycaemia it is possible to distinguish and quantify both first (010 minutes) and second-phase (10120 minutes) insulin secretion.5 The AIR can be determined using an IVGTT.6 Following the ingestion of a glucose load (OGTT), insulin appears to increase in a monophasic way, and the ratio between the plasma insulin and glucose increment at 30 minutes has been taken as a marker for the acute insulin response.7 Mathematical and modelling interpretation of the changes in plasma insulin/C-peptide concentrations after an OGTT have been developed to provide integrated8 as well as analytical9 assessment of beta-cell function. Employing these and other methods, an impairment in insulin secretion has been documented in the presence of overt hyperglycaemia, and most importantly, in the early stages of the natural history of type 2 diabetes when only a modest increase in plasma glucose levels can be ascertained. Finally, the progressive deterioration of glucose homeostasis that characterises the natural course of the disease has been ascribed to progressive loss of beta-cell function.10

Key words: type 2 diabetes, impaired acute insulin secretion, insulin resistance.

Introduction

Type 2 diabetes is characterised by concomitant impaired insulin action and defective insulin secretion. Insulin resistance is a common defect in the general population1 and although it is associated with an increased risk for development of type 2 diabetes2 and cardiovascular disease,3 it is the defect in insulin secretion that triggers the transition from normal to impaired glucose tolerance and diabetes. Impaired beta-cell function occurs early in the natural history of type 2 diabetes. A very early sign of such an impairment is the loss of first-phase insulin secretion in response to a glucose challenge that can be found when the fasting plasma glucose is as low as 6.1 mmol/L (110 mg/dL).4 The

Correspondence to: Dr Stefano Del Prato Department of Endocrinology & Metabolism, Section of Diabetes, Ospedale Cisanello, Via Paradisa, 2, 56124 Pisa, Italy. Tel: +39 050 995103; Fax: +39 050 541521 E-mail: delprato@immr.med.unipi.it

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ow insulin sensitivity and a selective loss of acute insulin release identify those individuals at the highest risk of developing type 2 diabetes. Normally, the rapid release of insulin after the ingestion of a meal is critical for post-prandial glucose regulation as first-phase insulin modulates suppression of endogenous glucose production and, therefore, limits meal-related plasma glucose excursions. The loss of first-phase insulin secretion contributes to the development of glucose intolerance. Indeed, postprandial hyperglycaemia represents the first and more evident perturbation of glucose homeostasis in about 60% of newly diagnosed type 2 diabetic patients. In these individuals, restoration of first-phase insulin secretion may result in more efficient inhibition of hepatic glucose production and improved glucose tolerance. In the light of these considerations, therapeutic intervention either alone or in combination with improvement of insulin resistance should be considered early in the course of the disease to prevent excessively rapid deterioration of glycaemic control. Br J Diabetes Vasc Dis 2005;5:198202

Natural history of type 2 diabetes and loss of insulin secretion

Disease progression was initially taken into account by the WHO diabetes classification that included NGT, IGT and diabetes mellitus. More recently, the new category IFG has been introduced. Both IFG and IGT are associated with increased risk for the development of diabetes. The IFG category recognises individuals with fasting plasma glucose ranging from 6.16.9 mmol/L (110125 mg/dL). The upper limit has been determined as a cut-off point associated with increased risk for diabetic microangiopathy and has an approximate correlation with two-hour post-OGTT plasma glucose. The lower limit (now 5.6 mmol/L [100 mg/dL]) is an arbitrary value chosen because a defect in first-phase insulin secretion often becomes apparent when plasma glucose values exceed above this figure. A defect in acute insulin response to IVGTT is generally observed in individuals with fasting plasma glucose > 6.4 mmol/L (> 115 mg/dL).4 Larsson et al. have found low insulin IVGTT response in IGT post-menopausal women,11 and shown that the degree of AIR is a main determinant of glucose tolerance at follow-up. This observation has been substantiated by longitudinal studies. In the San Antonio Heart Study12 both high fasting plasma insulin concentration (a proxy for insulin resistance) and modest increase of 30-minute post-OGTT plasma insulin levels (a proxy for beta-cell responsiveness to glucose) were independent predictors of the conversion from nor-

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Abbreviations AIR AUC DPP-IV EGP GLP-1 HOMA-IR IFG IGR IGT IVGTT -index i.v. NGT OGTT sc WHO acute insulin response area under the curve dipeptidyl peptidase IV endogenous glucose production glucagon-like peptide-1 Homeostatic model assessment insulin resistance impaired fasting glucose impaired glucose regulation impaired glucose tolerance intravenous glucose tolerance test integrated measure of beta-cell function intravenous normal glucose tolerance oral glucose tolerance test subcutaneous World Health Organization

Figure 1. Insulin resistance (HOMA) and insulin secretion (OGTT derived -index) in individuals with NGT, IGR: IFG and/or IGT, and type 2 diabetes mellitus

HOMA-IR Log [pmol insulin. 120min-1 m-2] 6 5 4 3 2 1 0 NGT IGR T2DM 6 5 4 3 2 1 0 NGT

-index

IGR

T2DM

Adapted from reference16

mal to impaired glucose tolerance. In a cohort of 348 women followed up over a 12-year period, the incidence of diabetes was greater in those who had the highest fasting plasma glucose and the lowest plasma insulin increments in response to IVGTT.13 The insulinogenic index is calculated as the ratio between the 30 minute plasma insulin to glucose increment after an OGTT and provides an index for the acute insulin response. Diabetes develops more frequently in individuals with low insulinogenic index.14 The prevalence of low insulinogenic index is greater in individuals with a positive family history of diabetes and in those with a strong genetic background such as offspring of diabetic parents or non-diabetic twin of a diabetic brother.14 The insulinogenic index represents a rough estimation of acute insulin release. Although a correlation exists between this index and AIR after IVGTT, the coefficient of correlation is low.15 A better correlation is found between a model-derived integrated measure of beta-cell function (-index) and IVGTT-generated AIR.8 We have recently determined the -index and insulin resistance (HOMA-IR) in individuals with normal (NGT n=126) and impaired glucose regulation (IGR: IGT and IFG) in response to a 75 gr OGTT.16 HOMA-IR was higher in IGR as compared to normal subjects (p<0.01) (figure 1). Basal insulin secretion increased as a function of HOMA-IR across the different categories of glucose tolerance, while the -index progressively decreased (p<0.05 vs. normals) (figure 1). Acute insulin release has been determined along with insulinmediated glucose utilisation in 17 Pima Indians in whom glucose tolerance was monitored over a five-year period.17 Transition from NGT to IGT was associated with an increase in body weight, reduction in insulin-mediated glucose utilisation as well as AIR. Transition from IGT to diabetes was associated with a modest worsening of insulin sensitivity and a much more dramatic impairment of AIR. In 31 subjects maintaining their NGT status over the same follow-up period, body weight and insulin resistance increased too, but the latter was compensated by concomitant increase in AIR. In a subsequent analysis, Weyer et al18 confirmed that both impaired insulin action and low AIR were

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independent and synergistic predictors for the progression from NGT to IGT and from IGT to diabetes. Finally, evidence has been gathered to indicate that beta-cell sensitivity falls already in the NGT range in association with rising two-hour post OGTT plasma glucose concentration19 supporting the concept that, related to glycaemic stimulus and degree of insulin sensitivity, there is a progressive decline in beta-cell function that can be ascertained in individuals who still have normal glucose tolerance.20

Pathophysiologic implications of loss of first-phase insulin secretion

Early-phase insulin secretion plays a critical role in the maintenance of glucose homeostasis. A strong negative relationship has been demonstrated between cephalic insulin release and initial glucose increment after commencement of a glucose infusion.21 After the ingestion of an oral glucose load, an inverse relationship was noted between 30-minute plasma insulin concentration (a marker for early insulin secretion) and two-hour plasma glucose levels.22 Conversely, a direct relationship was noted between two-hour plasma insulin and glucose concentrations. These observations indicate that early insulin rise is critical in restraining excessive glucose excursions after nutrient ingestion. In the presence of a weak early-phase insulin secretion, plasma glucose will progressively rise causing sustained insulin release. The dimension and time-course of insulin release during early-phase secretion is compatible with an effect on the liver rather than on peripheral tissues. Animal studies performed in Cherringtons laboratory support this view.23 In those experiments, plasma glucose concentration and EGP were measured in glucagon-infused dogs using a clamp technique to blocking endogenous insulin secretion. Under these conditions first, second, or both phases of insulin secretion were reconstructed to assess their relative contribution in controlling the glucose rise induced by glucagon infusion. The study showed that both first- and second-phase insulin secretion were critical in coun-

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CO PY RE PR (DI RI O AB GH DU E T CT TES M IO ) L ED N IM IN PR IT EW O ED S HI BI TE D
-75 -90

terbalancing the hyperglycaemic effect of glucagon, but isolated restoration of the early rise in plasma insulin level was sufficient to reduce the glucagon-mediated hyperglycaemia. Human studies also lend support to the central role of earlyphase insulin secretion in the modulation of EGP. Luzi et al. performed hyperglycaemic clamp studies in normal subjects together with radioactive glucose tracer infusion for measurements of glucose production and uptake.24 The acute elevation of plasma glucose concentration elicited the characteristic biphasic insulin release causing progressive EGP suppression and increase in glucose disposal in peripheral tissues. The selective abolition of the early-phase insulin secretion using somatostatin did not affect glucose utilisation. On the contrary, suppression of EGP was only 50% as compared with the control study (figure 2). Impaired EGP suppression was a direct consequence of the deficit of earlyphase insulin secretion, as proven by restoration of an early insulin rise in plasma. A similar experimental approach was used by CallesEscandon and Robbins,25 with the exception that an OGTT or an IVGTT was performed. Early insulin release was completely blocked by somatostatin infusion in both cases. The loss of early phase insulin secretion was associated with a deterioration of glucose tolerance. By using a more complicated technique, Basu et al26 came to a similar conclusion. Non-diabetic individuals were studied during somatostatin inhibition of endogenous insulin secretion, while exogenous insulin was infused to mimic the postprandial insulin profiles of a typical normal or diabetic individual. Simultaneously, glucose was infused in a pattern and amount that mimicked the systemic delivery rate normally observed after the ingestion of 50 g glucose. The delayed pattern of insulin delivery (i.e. loss of early-phase insulin secretion) was associated with higher glucose concentration with prolonged duration of hyperglycaemia. This alteration was mainly due to altered suppression of EGP. In summary, both animal and human studies support the critical physiological role of the early phase of insulin secretion in the maintenance of post-meal glucose homeostasis. This effect is primarily mediated at the level of the liver, allowing prompt inhibition of EGP and thereby restraining mealtime plasma glucose excursions.

Figure 2. Percent suppression of hepatic glucose production during a control 6.9 mmol/L (+125 mg/dL) hyperglycaemic clamp with (light purple bars) or without (purple bars) selective abolition by somatostatin infusion of first-phase insulin secretion. Abolition of first phase was associated with a significant impairment of suppression of endogenous glucose production both during early and late phase of the hyperglycaemic clamp

Early-phase
Percent reduction from basal hepatic glucose production 0 -15 -30 -45 -60

Late-phase

* *

* p<0.005 or less

Adapted from reference24

Pathogenic role and reversibility of the loss of earlyphase of insulin secretion

The early development of the defect in acute insulin secretion and its physiopathologic implications suggest that restoration of early-phase insulin secretion might represent a rational approach in diabetes prevention.17 Only a few studies have addressed such an opportunity. In the Malm Study27 IGT subjects were randomised to an intervention with tolbutamide or placebo while adequate diet and physical activity counselling was ensured in all individuals. During the 10-year follow-up period, diet alone was associated with a 58% reduction in diabetes conversion, a result quite similar to that reported in the more recent Diabetes Prevention Program28 and Diabetes Prevention Study.29 Only one case of diabetes was recorded among those receiving sulphony-

lurea. Though intriguing, these results have not been confirmed by other studies. The reversibility of first-phase insulin loss is likely to depend on the interaction between the intimate nature of the alteration and the negative effects of interfering factors such as lipo- and gluco-toxicity. Seventy-two-hour artificial elevation of basal plasma glucose levels at (6.1 mmol/L [110 mg/dL]) does not affect beta-cell function in young normal volunteers.30 However, a sustained increase in plasmafree fatty acid levels impairs insulin secretion in non-diabetic subjects genetically predisposed to develop type 2 diabetes.31 On the other hand, this observation leaves room for a positive effect of improved metabolic control on residual beta-cell function. If the loss of early insulin release plays a major role in the pathogenesis of postprandial hyperglycaemia, therapeutic intervention to restore it is expected to improve glucose control in type 2 diabetic patients. Evidence for this approach has been generated by pre-meal exogenous insulin administration to restore the acute rise in plasma insulin. For this purpose, a similar insulin dose was given i.v. at mealtimes to type 2 diabetic patients (i) over 30 minutes at the beginning of a meal (i.e. restoration of early insulin increase); or (ii) 30 minutes after meal ingestion; and (iii) as a constant infusion over the entire duration of the study.32 A significant improvement in post-meal glucose tolerance was apparent only with early administration of insulin. These results have been replicated in our laboratory comparing the effect of similar doses (0.075 U/kg lean body mass) of regular insulin and the insulin analogue lispro given s.c. to type 2 diabetic patients prior to a 50 g OGTT.33 In spite of comparable incremental AUCs, the time-course of plasma insulin concentration was very different. After injection of regular insulin, plasma

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Figure 3. Area under the incremental curve (AUC) of plasma insulin (left hand panel) and glucose (right hand panel), and plasma insulin concentration at 60 minutes (middle panel) after a 50 g oral glucose load preceded by subcutaneous injection of an equivalent dose (0.075 U/kg lean body mass) of regular (purple bars) and lispro (light purple bars) insulin

Plasma insulin incremental area 42 AUC (nmol/l/300 minute) 36 30 24 18 12 6 0

* p<0.05 Adapted from reference33

60-minute plasma insulin 600 AUC (mol/l/300 minute) 900 750 600 450 300 150 0

Plasma glucose incremental area

450 (pmol/l)

*
300

150

Figure 4. First- and second-phase insulin secretion during hyperglycaemic clamp (black bars: +7.5, light purple bars: +10, and purple bars: +15 mmol/L) in control subjects and type 2 diabetic patients after 36 weeks treatment with diet or gliclazide (median dose 80 mg/day)

1st-phase 120 100 Plasma insulin (mU/l) 80 60 40 20 0

Controls Diet Gliclazide Type 2 diabetic patients

Adapted from reference34

insulin peaked at 120 minutes, while with lispro the peak occurred at 60 minutes. Plasma insulin concentration during the last three hours of the study was lower with lispro compared to regular insulin. The plasma glucose incremental AUC was 46% lower with lispro (715+109 vs. 389+109 pmol/300 minute; p<0.01) (figure 3). The study was carried out in combination with a double tracer technique for calculation of the rates of glucose utilisation and production. While there was no difference in the two studies in the overall rate of glucose disposal, the rate of EGP was suppressed in a prompter and more profound manner

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Insulin Lispro Insulin Lispro Insulin Lispro

250 2nd-phase Plasma insulin (mU/l) 200 150 100 50 0

Key messages

Progressive loss of beta-cell function characterises the deterioration of glucose homeostasis during the natural course of type 2 diabetes A progressive decline of beta-cell function in insulin insensitive individuals with normal glucose tolerance precedes development of type 2 diabetes Early phase insulin secretion is critical to maintain normal glucose homeostasis

Controls Diet

Gliclazide

Type 2 diabetic patients

when lispro was administered, accounting for the lower postprandial glucose profile. A main limitation of exogenous insulin is the inability to restore normal porto-systemic gradient of the hormone, as achieved by stimulation of endogenous insulin secretion. For over four decades, sulphonylureas have been used to enhance insulin secretion in patients with type 2 diabetes, with some of these agents possibly exerting a stimulatory effect on early-phase insulin secretion. Hosker et al34 reported that first-phase insulin secretion in response to different degrees of hyperglycaemia was enhanced by administration of gliclazide (figure 4). Interestingly, gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity.35 New non-sulphonylurea secretagogues have been developed that should increase first-phase insulin secretion in a more specific manner,36 though their potency is lower than desired. GLP-1

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potently stimulates glucose-dependent insulin secretion while it inhibits glucagon secretion when administered to type 2 diabetic patients.37 However, native GLP-1 is rapidly degraded by DPPIV after parenteral administration. Therefore, GLP-1 receptor agonists have been developed which possess resistance to enzymatic degradation as well as having long-acting effects.38 Alternatively, inhibition of GLP-1 degradation by DPP-IV represents a complementary therapeutic approach.39

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