Activity of the Entero Insular Axis and Incretin Hormones in Type Diabetic Patients

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Reduced Incretin Effect in Patients with Type 2 Diabetes

In healthy human subjects oral glucose elicits a considerably higher insulin secretory response than does intravenous glucose (even if leading to the same glycemic increments). This incretin effect is substantially reduced or even completely lost in patients with type 2 diabetes [86]. The reduction in the incretin effect probably is an acquired defect, since it is also found in patients with diabetes secondary to chronic pancreatitis, whereas chronic pancreatitis without diabetes is characterized by a normal incretin effect [87].

Secretion of Incretin Hormones in Patients with Type 2 Diabetes

Cross-sectional analyses of larger cohorts suggest that there is a slight reduction in postprandial GLP-1 secretion following the ingestion of a mixed meal in patients with type 2 diabetes. Subjects with impaired glucose tolerance display intermediate results between healthy controls (normal response) and type 2-diabetic patients (reduced response) [88]. This is true for both total and intact GLP-1 [36]. However, the overall difference is small, and concerns the second and third hour after starting meal ingestion, whereas the characteristic differences in insulin secretory pattern are found in the early period after glucose or meal ingestion [89].

Table 1. Typical features of the type 2 diabetic phenotype and the complementary activity profile of GLP-1, incretin mimetics, and DPP-4 inhibitors. (Modified from Drucker and Nauck 2006 [145]).

Characteristics of type 2 diabetes

Biological actions of incretin-related hormones/medications

Native GLP-Ia

Incretin mimetics Exenatide Liraglutide

DPP-4 inhibitors Sitagliptin Vildagliptin

Defective insulin secretion

Stimulation of insulin secretion

Yes [11]

Yes [221]

Yes [222]

Yes

Yes [150]

(glucose-dependent)

Lack of early phase*1

Restoration of early phase

Yes [223]

Yes [224]

Not tested

Not tested

Not tested

Delayed insulin secretion after meals [225]

More rapid insulin secretion after meals'

Yes [113. 226]

Yes [221]

Yes [222]

Yes

Yes [150]

Reduction in the incretin effect [86]

Replacement of incretin activity/enhanced

Yesc

Yesc

Yesc

Not tested.

Not tested.

incretin effect

but probable

but probable

Hyperglucagonemia [227]

Suppression of glucagon

Yes [11]

Yes [221]

Yes [222]

Yes

Yes [150]

Hypoglycemia counter-regulation

Glucagon secretion, when plasma

Yes [68]

Yes [228]

Yes [229]

Not tested

Not tested

glucose is low

Reduced (3-cell insulin content

Stimulated synthesis of proinsulin

Yes [230]

Yes

Yes

Yes (?)

Yes (?)

Reduced P cell mass [193. 231]

Increase in (3-cell masse

Yes [232]

Yes [199]

Yes [205]

Yes [208]

Yes [216]

Differentiation of islet precursor

Yes [214]

Yes

Yes

Unknown

Unknown

cells into |3-cellse

Enhanced (3-cell apoptosis [193]

Inhibition of P-cell apoptosise

Yes [63. 213]

Yes [233]

Yes [234]

Probable

Probable

[207]

Normal, slowed, or accelerated [235] gastric

Deceleration in gastric emptying

Yes [70]

Yes [175]

Yes [222]

Not tested

Marginal

emptying

[165.182]

High energy intake/obesity [236]

Suppression of appetite/induction

Yes [74]

Probable

Yes [157]

No obvious

No obvious

of satiety

effect

effect

Weight loss

Yes [114]

Yes

Yes [158]

No weight

No weight

[119-121]

change

change [153]

aGLP-l may be in a "glycine-extended" form [7-37] or the predominant "amidated" form. [7-36] amide; both forms have similar biological activities.

bA separate early-phase insulin response is only seen under artificial conditions leading to a rapid rise in glucose concentrations (glucose bolus injection, "squarewave stimulus" when starting a hyperglycemic clamp).

'Shown by an improvement (normalization) of postprandial glucose excursions. ''By definition. GLP-1 and incretin mimetics replace incretin activity.

eThese actions have only been reported from animal or in vitro (e.g.. islet) studies. Methods to assess human (3-cell mass in vivo are not available.

Therefore, it cannot be considered likely that the slight reduction in postprandial GLP-1 secretion in patients with type 2 diabetes has any immediate impact on glycemic control. Along the same lines, any administration of GLP-1 receptor agonists should not be simply considered a replacement of an essential hormone (e.g. GLP-1) that is lacking in patients with type 2 diabetes.

GIP secretion in patients with type 2 diabetes has been reported as exaggerated [90], normal (on average) [91], or reduced [88]. In all cases, the differences were small in comparison with appropriate control subjects and are not likely to indicate any importance for the pathophysiology of the entero-insular axis in type 2 diabetes. Certainly, there is no complete lack in GIP in patients with type 2 diabetes.

Insulinotropic Activity of GIP and GLP-1 in Patients with Type 2 Diabetes

While the interaction of both GIP and GLP-1 with their respective receptors on healthy pancreatic endocrine P-cells leads to cAMP production and the augmentation of glucose-stimulated insulin release in a very similar manner [92], the insulinotropic activity of GIP is almost completely lost in patients with type 2 diabetes [10-13,93]. This does not appear to indicate a lack of expression of GIP receptors on type 2-diabetic P-cells, since a bolus injection of GIP still elicits some insulin secretory response [13]. However, prolonged infusion, even of highly pharmacological doses of GIP, is unable to meaningfully stimulate insulin secretion. This certainly is the fundamental defect underlying the reduced incretin effect in patients with type 2 diabetes. The patho-physiology of the entero-insular axis in type 2 diabetes is outlined elsewhere in more detail [94,95].

On the other hand, a considerable proportion of the insulinotropic activity of GLP-1 as found in healthy subjects is preserved in patients with type 2 diabetes (Table 1). Physiological concentrations of GLP-1 (as found after meal ingestion), however, have little if any effect on insulin secretion in patients with type 2 diabetes [11].

Upon a closer look, the insulinotropic activity of GLP-1 is also somewhat reduced in patients with type 2 diabetes compared with healthy control subjects [96]. However, even a relatively low dose of GLP-1 can acutely restore the ability of P-cells to respond to increasing glucose concentrations with an insulin secretory response similar to healthy subjects. Nevertheless, the insulin response remains at approximately 20-25% relative to the effect in healthy subjects exposed to the same GLP-1 doses and concentrations [96]. This partial preservation of insulin secretory effects is sufficient to make GLP-1 a potent insulinotropic agent in patients with type 2 diabetes.

Pharmacological doses of GLP-1 display the full spectrum of activities also in patients with type 2 diabetes (Fig. 2, Table 1). This includes effects on insulin [11,97] and glucagon [11] secretion, gastric emptying [20,97], appetite, and meal size [76]. As a consequence, antidiabetic properties of pharmacological doses of GLP-1 have been examined in patients with type 2 diabetes.

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