Pharmacological Stimulation of Insulin Secretion

Insulin Secretion as Modified by Sulfonylureas The main drugs able to stimulate insulin secretion are the sulfonylureas.

These compounds have been used in the management of type 2 diabetes since 1955 and, when properly utilized, are easy to use and appear to be effective

and safe. It is estimated that 30–40% of diabetic patients are taking oral sulfonylureas. Indications and contraindications for sulfonylureas are shown in tables 1 and 2, respectively.

Table 1. Patients candidate for sulfonylurea treatment Most patients with type 2 diabetes, not well controlled with dietary restriction and exercise

Children and adults with the MODY (maturity-onset diabetes of youth) type of diabetes Obese-diabetic patients with marked insulin resistance Lean type 2 diabetic patients with preserved insulin secretory capacity

Table 2. Contraindications to sulfonylurea treatment Patients with type 1 diabetes

Patients with pancreatic diabetes Patients with an acute illness or stress or undergoing surgery Patients with hepatic or liver diseases Patients predisposed to hypoglycemia:

Underweight or malnourished Elderly

Diabetic pregnancy: Potential teratogenicity Perinatal mortality Severe neonatal hypoglycemia

Diabetic female patients during lactation Patients with a history of severe adverse reactions to sulfonylureas

Different Sulfonylureas The first oral hypoglycemic drug was synthesized in 1926 by altering the

guanidine molecule. The sulfonylureas used today are derived from this native molecule. The ‘first-generation’ sulfonylureas, which were developed initially, are effective in large doses, while the ‘second-generation’ drugs, developed more recently, are effective in smaller doses. Some sulfonylureas, such as tolbutamide,

Table 3. Main characteristics of sulfonylureas Compound

Dose, mg/day Doses q.d. Duration of Metabolism/ hypoglycemic excretion effect, h

First generation Acetohexamide

12–18 Liver/kidney Tolbutamide

6–12 Liver Chlorpropamide

1 60 Kidney Tolazamide

12–14 Liver Second generation

Glibenclamide (or glyburide)

16–24 Liver/kidney Glyburide, micronized

12–24 Liver/kidney Glipizide

12–24 Liver/kidney Gliclazide

10–20 Liver/kidney Gliquidone

6–12 Liver Glimepiride

1 D24 Kidney

4–6 Liver 1 Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinide family.

Repaglinide 1 0.5–16

have a short duration of action (6 h), others, such as chlorpropamide, have a long duration of action (up to 60 h), several others show an action of intermediate duration. Some characteristics of the sulfonylureas which are or have been in clinical use are summarized in table 3.

‘First-Generation’ Sulfonylureas. Tolbutamide has a ‘short’ duration of action (see table 3) and is carboxylated by the liver to a totally inactive derivative. Being metabolized only in the liver, this compound may be useful in nephropathic diabetic patients.

Tolazamide has a more potent hypoglycemic activity than tolbutamide and an ‘intermediate’ duration of action (see table 3). It is metabolized only by the liver with the production of some very little active metabolites excreted in the urine (85%). It is safer in the elderly and in nephropathic diabetic patients. Tolazamide also has a diuretic action.

Chlorpropamide has a more potent hypoglycemic activity than tolbutamide and a ‘very long’ duration of action (see table 3), and therefore it can induce more hypoglycemic episodes than tolbutamide. It is hydroxylated by the liver with production of some active metabolites excreted in the urine (by 80–90%) and, thus, is contraindicated in the elderly and in nephropathic diabetic patients. Several side or toxic effects may occur with chlorpropamide, Chlorpropamide has a more potent hypoglycemic activity than tolbutamide and a ‘very long’ duration of action (see table 3), and therefore it can induce more hypoglycemic episodes than tolbutamide. It is hydroxylated by the liver with production of some active metabolites excreted in the urine (by 80–90%) and, thus, is contraindicated in the elderly and in nephropathic diabetic patients. Several side or toxic effects may occur with chlorpropamide,

Acetohexamide has a more potent hypoglycemic activity than tolbutamide and an intermediate duration of action. It is reduced by the liver to 1-hydroxy- hexamide which is a potent hypoglycemic drug, excreted by 60% in the urine. Thus, it is contraindicated in the elderly and in nephropathic diabetic patients. Acetohexamide also has diuretic and uricosuric actions.

‘Second-Generation’ Sulfonylureas. Glyburide or glibenclamide has been used since 1969. It has a 50–100 times more potent hypoglycemic activity than the ‘first-generation’ drugs and has a relatively long duration of action. It is metabolized by the liver to several both inactive and mildly active metabolites, excreted partially in the urine (50%) and partially in the bile (50%). It may induce severe hypoglycemic episodes and is contraindicated in the elderly and in nephropathic diabetic patients. Glyburide absorption is not affected by food but it takes 30–60 min to achieve adequate plasma levels, so that this drug should be taken before the morning meal.

Glipizide has been used since 1973, has a 50–100 times more potent hypoglycemic activity than the ‘first-generation’ drugs (comparable to that of glyburide) and has an ‘intermediate’ duration of action (see table 3). It is metabolized by the liver to several inactive metabolites, excreted in the urine (by 68%) and in the feces (by 10%). It may induce severe hypoglycemic episodes (similarly to glyburide) and is contraindicated in the elderly and in nephropathic diabetic patients. The absorption of glipizide is delayed by about 30 min when it is ingested with a meal, so that it is recommended to take the drug

30 min before meals. Glipizide has a greater effect than glyburide in raising postprandial plasma insulin level and lowering postprandial plasma glucose

level while glyburide has a better effect than glipizide in raising fasting insulinemia and reducing fasting glycemia (probably, reducing fasting hepatic glucose

production). For this metabolic difference, a ‘combined’ administration of the two sulfonylureas was suggested.

Gliclazide has a potent hypoglycemic activity (comparable to that of glyburide and glipizide) and has an ‘intermediate’ duration of action. It is metabolized by the liver to several probably inactive metabolites, excreted in the urine (by 60–70%). It has been suggested that gliclazide exerts antiplatelet aggregating activity, with a potential preventing effect on diabetic microangi- opathy, although this effect has not been confirmed.

Gliquidone has a short duration of action (the mean half-life was approxi- mately 1.2 h and the mean terminal half-life was 8 h), is metabolized in the liver to totally inactive or minimally active derivatives, and is excreted in the intestine (by about 100%). For these reasons, gliquidone is safer in the elderly Gliquidone has a short duration of action (the mean half-life was approxi- mately 1.2 h and the mean terminal half-life was 8 h), is metabolized in the liver to totally inactive or minimally active derivatives, and is excreted in the intestine (by about 100%). For these reasons, gliquidone is safer in the elderly

Efficacy and Interactions. Good response with sulfonylureas will occur in 70–75% of patients during the first years of treatment, provided that the patient selection is appropriate. Primary failure occurs in 15–25% of cases and may depend on a poor selection of the patients (unrecognized type 1 diabetic patients treated with sulfonylureas). Chronic therapy may be associated with progressively less beneficial effects (secondary failure), sometimes as result of intercurrent factors which impair insulin action and secretion (such as stress, infections, dietary disregard, etc.) (see also chapter III on Insulin Resistance and Its Relevance to Treatment). The response to the hypoglycemic drugs may be restored with the disappearance of the intercurrent event. All sulfonylureas are bound to serum albumin and, since a large number of drugs may compete for ionic binding sites on albumin, sulfonylureas can influence the effect of many drugs (and these drugs, conversely, can influence the effect of sulfonylureas). The physician must understand potential interactions with a number of commonly used drugs, that may significantly alter the activity of the sulfonylureas both diminishing (diuretics,

b -blockers, corticosteroids, estrogens, indomethacin, alcohol, rifampicin, etc.) or increasing (sulfonamides, salicylates, clofibrate, chloramphenicol, MAO inhibitors, probenecid, allopurinol, b-blockers, alcohol, etc.) their hypoglycemic effect. It is noteworthy that some drugs (such as b-blockers and alcohol) can alter sulfonylureas activity in opposite directions. Sulfonylureas of ‘second generation’ may have less interactions than those of the ‘first generation’.

Some data of literature demonstrate that serum levels of sulfonylureas (tolbutamide, chlorpropamide, glyburide and gliquidone) in treated diabetic patients show extremely interindividual variations, with no correlation between the dose and the plasma level.

Mechanism of Sulfonylurea Action Acute Effects on Insulin Secretion. Sulfonylureas act primarily by acutely

stimulating release of insulin from pancreatic b-cells (obviously, in presence of functioning pancreatic islets), and this stimulation of insulin secretion is a stimulating release of insulin from pancreatic b-cells (obviously, in presence of functioning pancreatic islets), and this stimulation of insulin secretion is a

Available data suggest that sulfonylureas bind to a specific receptor (closely associated with the ATP-sensitive K + -channels) on the outside of plasma membrane of the b-cells. Recent studies with human pancreatic islets showed

that 3 H-glibenclamide binds to saturable sites in islet membrane preparations in a linear fashion. This binding was both temperature- and time-dependent. Scatchard analysis of the equilibrium binding data indicated the presence of a single class of saturable, high-affinity binding sites. The displacement experiments showed the following rank order of potency of the oral hypoglycemic agents tested: glibenclamide > glimepiride ? tolbutamide ? chlorpropamide A metformin. This binding potency order was parallel with the insulinotropic potency of the evaluated compounds. Glimepiride has been reported to bind to a 65-kDa subunit of the sulfonylurea receptor. This charac- teristic may entail a minor effect of the K-channel in other tissues, such as myocardium (where the closure of K-channels may interfere with the repolar- ization process).

Upon binding to their receptors, sulfonylureas inhibit the K + -channels, diminish K + efflux and cause depolarization of the plasma membrane. This depolarization induces voltage-dependent Ca 2+ -channels to open and extracel- lular Ca 2+ to enter the cell. Increased cytoplasmic Ca 2+ stimulates the fusion of the secretory granule membrane with cell membrane, followed by extrusion of insulin outside the cell (exocytosis) (see also fig. 1).

Metabolic studies demonstrate that sulfonylureas stimulate the first phase of insulin release and have little effect on the second phase. They can act in

the absence of glucose but also may potentiate glucose-mediated insulin release. As consequence of the stimulation of secretion, sulfonylureas can induce mor- phological alterations of the b-cells such as degranulation, loss of zinc and aspects of emiocytosis.

Chronic Effects on Insulin Secretion. Whether chronic sulfonylurea treatment results in increased insulin secretion is a controversial problem. The finding that after chronic treatment of type 2 diabetic patients insulinemia returns to pretreatment level, without deterioration of glucose control, suggests long-term extrapancreatic effects of sulfonylureas. The lower plasma glucose achieved with sulfonylurea drugs in type 2 diabetic patients might be expected to stimulate less insulin secretion (blood glucose is the major stimulus to insulin release), and this can explain the inability of some studies to demonstrate the chronic effect of sulfonylurea in stimulating insulin secretion. Available literature data, however, do not support the concept that the improvement of glycemia during chronic sulfonylurea treatment can be attributed solely to an increased insulin secretion.

Table 4. Extrapancreatic effects of sulfonylureas Hormonal effects

Potentiation of insulin action on skeletal muscle and adipose tissue glucose transport Potentiation of insulin action on hepatic glucose production (activation of glycogen synthase

and glycogen synthesis) Decrease of hepatic insulin extraction Decrease of insulin degradation (inhibition of insulinase activity) Stimulating effect on gastrointestinal hormone release

Direct metabolic effects Insulin receptors (partial restoration of their number in plasma membrane in type 2 obese-

diabetic patients) Liver (increase in fructose 2,6-bisphosphate; increase in glycolysis; decrease in gluconeogen- esis; decrease in long-chain fatty acid oxidation) Skeletal muscle (increase of glucose and amino acid transport; increase of fructose 2,6- bisphosphate) Myocardial tissue (increase of contractility; increase of oxygen consumption; increase of

glycogenolysis; decrease of Ca 2+ -ATPase; increase of glucose transport and glycolysis; increase of phosphofructokinase activity and pyruvate oxidation)

Adipose tissue (increase in glycogen synthase; inhibition of lipolysis, increase in glucose transport) Platelet arachidonic acid metabolism (inhibition of cycloxygenase and 12-lipoxygenase path- ways)

Other Effects. Sulfonylurea treatment does not appear to stimulate proinsulin biosynthesis. On the other hand, studies performed with in vivo and in vitro animal perfused pancreases, or with isolated perifused islets and islet- cell cultures, reported an acute and chronic sulfonylurea-induced inhibition of the biosynthesis of proinsulin (through unknown mechanisms). Sulfonylureas, acutely or chronically, do not alter glucagon secretion both in normal subjects and diabetic patients. Sulfonylureas appear to stimulate pancreatic d-cell soma- tostatin release (with unclear physiological effect).

Extrapancreatic Effects of Sulfonylureas. Diverse in vitro and in vivo extrapancreatic effects of sulfonylureas have been reported over the last 30

years (most of which, however, were obtained with drug concentrations larger than those achieved in therapeutic use) (table 4). These effects of sulfonylureas

are due to direct actions on liver and/or muscle and, occurring in the absence of changes in insulin binding, are probably mediated by postreceptor events. As a whole, the extrapancreatic effects of sulfonylureas are of minor clinical significance. A possible exception is glimepiride, which may exert more signifi- cant extrapancreatic actions, including activation (through dephosphorylation) of GLUT-4.

Table 5. Sulfonylurea side or toxic effects Hematologic reactions (agranulocytosis, bone marrow or red cell aplasia, hemolytic anemia)

Skin reactions (rash, pruritus, erythema, purpura, photosensitivity) Hypersensitivity reaction (rush, fever, arthralgia, angiitis, jaundice, etc.) Alcohol-induced flushing (most frequently associated with chlorpropamide treatment) Gastrointestinal complaints (nausea, vomiting, jaundice or hepatitis or cholestasis) Antithyroid activity Diuretic effect or antidiuresis with hyponatremia Cataract formation (reported in some dogs treated with high doses of glimepiride) Teratogenicity

Side or Adverse Effects of Sulfonylureas. The most important adverse effect of sulfonylureas is hypoglycemia which, although occurring less often than

with insulin, when it occurs it tends to be more severe, prolonged and sometimes fatal. The incidence of sulfonylurea-induced hypoglycemia is 0.19–4.2/1,000 treatment years (compared to 100/1,000 patients/year for insulin-induced hypoglycemia) and is most frequent in patients taking long-acting drugs (such as glyburide and chlorpropramide) which, for this reason, should be avoided in patients with predisposing conditions (the best treatment of hypoglycemia is prevention). The case fatality rate of hypoglycemia induced by sulfonylureas is 4.3% (see also chapter VIII on Clinical Emergencies in Diabetes. 2: Hypogly- cemia). It is noteworthy that sulfonylureas predispose to hypoglycemia during and after exercise. In this regard, it has been claimed that glimepiride maintains

a more physiological regulation of insulin secretion during physical exercise, with less risk of hypoglycemia. Other sulfonylurea side effects or toxic reactions occur at low rate (1.5% for glyburide) (table 5) and appear within the first 2 months of treatment. The chlorpropamide alcohol flushing (CPAF), occurring in 30–40% of type 2 and 10% of type 1 diabetic patients, is linked to a genetic predisposition to diabetes development (autosomic trait) and can be considered a good genetic marker of type 2 diabetes mellitus.

Other Drugs Modifying Insulin Secretion Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinide

family, a new class of drugs with insulin secretory capacity which exert a rapid- and also short-acting effect, thus entailing reduced risk of long-lasting,

and hence dangerous, hypoglycemia. Repaglinide appears to bind to receptor and hence dangerous, hypoglycemia. Repaglinide appears to bind to receptor

animals, healthy volunteers and patients with type 2 diabetes mellitus. Repagli- nide is rapidly absorbed and eliminated, which may allow a relatively fast onset and offset of action. Excretion occurs almost entirely by nonrenal mechanisms. In comparative clinical trials in patients with type 2 diabetes mellitus, repaglinide 0.5–4 mg twice or 3 times daily before meals provided similar glycemic control to glibenclamide (glyburide) 2.5–15 mg/day. Addition of repaglinide to existing metformin therapy resulted in improved glycemic control. In contrast with glibenclamide, use of repaglinide allowed patients to miss a meal without apparently increasing the risk of hypoglycemia.

GLP-1 has insulinotropic action, which may explain the increased insulin response after oral compared to intravenous glucose administration, and exerts several other functions such as reduction of glucagon concentration, reduction of gastric emptying, stimulation of proinsulin biosynthesis and reduction of food intake (upon intracerebroventricular administration in animals). On these grounds, GLP-1 seems to offer an interesting perspective in treatment of diabetic patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of type 2 diabetes. This peptide is able to lower and perhaps normalize fasting hyperglycemia and to reduce postprandial glycemic increments (especially in type 2 diabetic patients) but its usefulness is not completely established. Due to rapid proteolytic cleavage, the half-life of GLP-1 is too short for therapeutical use with subcutaneous injections. GLP-1 analogues with different pharmacokinetic properties (or some preparations that could

be orally administered) are in development. Given the large amount of GLP-1 present in L-cells, it appears worthwhile to look for some agents that could ‘mobilize’ this endogenous pool of the ‘antidiabetogenic’ gut hormone GLP-1. Interference with sucrose digestion using a-glucosidase inhibition moves nutri- ents into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release.

Antiarrhythmic agents with Vaughan Williams class I a action have been found to induce a sporadic hypoglycemia. Recent investigation has revealed that these drugs induce insulin secretion from pancreatic b-cells by inhibiting ATP-sensitive K + (K-ATP) channels in a manner similar to sulfonylurea drugs. It is possible that in the future, pharmacological compounds will be found that may act on GK and improve b-cell insulin secretion.

Pharmacological Stimulation of Insulin Secretion