Pancreatic beta cell function

INTRODUCTION — Insulin is a peptide hormone composed of 51 amino acids that is synthesized, packaged, and secreted in pancreatic beta cells. The mechanisms of insulin secretion and measurements of beta cell function in normal subjects and patients with various diseases will be reviewed here. The mechanisms of insulin action are discussed separately. (See "Insulin action".)

ANATOMY — Pancreatic beta cells are found in the islets of Langerhans, which are of various size and contain a few hundred to a few thousand endocrine cells. Islets are anatomically and functionally separate from pancreatic exocrine tissue (which secretes pancreatic enzymes and fluid directly into ducts that drain into the duodenum). Normal subjects have approximately one million islets that, in total, weigh 1 to 2 grams and constitute 1 to 2 percent of the mass of the pancreas.

Islets vary in size from 50 to 300 micrometers in diameter. They are composed of several types of cells. At least 70 percent are beta cells, which are mostly localized in the core of the islet. These cells are surrounded by alpha cells that secrete glucagon, smaller numbers of delta cells that secrete somatostatin, and PP cells that secrete pancreatic polypeptide (figure 1). All of the cells communicate with each other through extracellular spaces and through gap junctions. This arrangement allows cellular products secreted from one cell type to influence the function of downstream cells. As an example, insulin secreted from beta cells suppresses glucagon secreted from alpha cells.

A neurovascular bundle containing arterioles and sympathetic and parasympathetic nerves enters each islet through the central core of beta cells. The arterioles branch to form capillaries that pass between the cells to the periphery of the islet and then enter the portal venous circulation.

INSULIN SYNTHESIS AND SECRETION — Insulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum. Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus, where it is packaged into secretory granules located close to the cell membrane. Proinsulin is cleaved into equimolar amounts of insulin and C-peptide in the secretory granules (figure 2). The process of insulin secretion involves fusion of the secretory granules with the cell membrane and exocytosis of insulin, C-peptide, and proinsulin.

Basal (unstimulated) insulin secretion is pulsatile, with a periodicity of 9 to 14 minutes [1]. Loss of pulsatile secretion is one of the earliest signs of beta cell dysfunction in patients destined to have type 1 diabetes [2].

Role of glucose — The primary regulator of insulin secretion is glucose, which acts both directly and indirectly by augmenting the action of other insulin secretagogues. Glucose is taken up by the beta cells via glucose transporters (GLUT2), the expression of which is increased by chronic exposure to high glucose concentrations [3,4]. It is then phosphorylated to glucose-6-phosphate by an islet-specific glucokinase (figure 3) [5].

Glucokinase acts as a glucose sensor of the beta cells [5,6]. Mutations in this enzyme lead to one of the forms of maturity-onset diabetes of the young (MODY2) [7], while deletion of one of the glucokinase genes in mice reduces insulin secretion, and deletion of both genes causes perinatal death due to severe hyperglycemia [8,9]. Glucokinase-deficient islets respond almost normally to arginine and partially to sulfonylurea drugs [9]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Monogenic diabetes (formerly called maturity onset diabetes of the young)'.)

The subsequent metabolism of glucose increases cellular adenosine triphosphate (ATP) concentrations and closes ATP-dependent potassium (KATP) channels in the beta cell membrane, causing membrane depolarization and influx of calcium. The rise in intracellular free calcium promotes margination of the secretory granules, their fusion with the cell membrane, and release of their contents into the extracellular space. The importance of the KATP channels in the regulation of insulin release is illustrated by two observations:

●Transgenic mice in which the KATP channels have reduced sensitivity to ATP and therefore remain open, develop hypoinsulinemia, severe hyperglycemia, and ketoacidosis within two days after birth [10].

●The extracellular surface of the KATP channels contains receptors that bind sulfonylureas (and other insulin secretagogues like repaglinide) that facilitate closure of the channels [11]. These drugs are useful in the treatment of type 2 diabetes because they increase insulin secretion. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)

The KATP channel mentioned above is also an important regulator of insulin release. This channel is a functional complex of the sulfonylurea 1 receptor (SUR1) and an inward rectifier potassium channel subunit, Kir6.2. Mutations in either the SUR1 gene or the Kir6.2 gene lead to loss of KATP activity; as a result, the cell is persistently depolarized, resulting in calcium influx, high cytosolic calcium concentrations, and release of insulin, resulting in a syndrome called persistent hyperinsulinemic hypoglycemia of infancy [12]. Mutations in the Kir6.2 and, to a smaller extent, SUR1 genes have also been identified in patients with permanent neonatal diabetes mellitus; treatment with sulfonylurea medication can restore insulin sensitivity in these patients [13,14]. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism" and "Neonatal hyperglycemia".)

In addition, beta cells have membrane receptors for various peptides, hormones, and neurotransmitters that can modulate the secretion of insulin [15]. Other factors within the beta cells also contribute to insulin release including hepatocyte nuclear factors 4-alpha, 1-alpha, and 1-beta; mutations in these proteins have been associated with MODY1, MODY3, and MODY5, respectively. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Monogenic diabetes (formerly called maturity onset diabetes of the young)'.)

The beta cells also have insulin receptors that may participate in the regulation of glucose-induced insulin secretion. Mice with an inactivated insulin receptor gene in the beta cells have a selective loss of insulin secretion in response to glucose [16].

Insulin response to glucose — Rapid increases in blood glucose concentration (eg, after bolus intravenous administration of glucose) cause a rapid burst of insulin secretion that peaks within three to five minutes and subsides within 10 minutes (called "first-phase" insulin release) (figure 4) [17,18]. This burst is probably due to the release of insulin from granules that were directly adjacent to the cell membrane. If the blood glucose concentration remains high, then the rise in insulin secretion is sustained (often called "second-phase" insulin release). This sustained increase is due to the release of both stored insulin and newly synthesized insulin. A decrease followed by an absence of first-phase insulin secretion in response to intravenous glucose is an early feature of beta cell dysfunction in patients with type 2 diabetes, occurring when fasting blood glucose concentrations range between 100 to 115 mg/dL (5.6 to 6.4 mmol/L) [19]. This loss of first-phase insulin response to glucose as blood glucose concentrations increase over prolonged periods of time has been ascribed to glucose toxicity of the beta cell secondary to chronic oxidative stress [20].

In addition to directly stimulating insulin release, glucose potentiates the effects of other insulin secretagogues. As an example, the amount of insulin released in response to the intravenous administration of arginine varies with the blood glucose concentration at the time [21]. The acute insulin response to arginine increases in an approximately linear manner as blood glucose concentrations increase from 100 to 300 mg/dL (5.6 to 16.7 mmol/L), reaching a plateau above 450 mg/dL (25 mmol/L) (figure 5) [22]. In contrast, rising blood glucose concentrations cause progressive suppression of the serum glucagon response to arginine [21].

MEASURES OF INSULIN SECRETION AND BETA CELL MASS — There are several metabolic methods of measuring insulin secretion and estimating beta cell mass, including fasting blood glucose, serum insulin concentration, oral and intravenous glucose tolerance tests, and arginine stimulation. In human experiments, measurements of the acute serum insulin response to glucose (AIRgluc) and arginine (AIRarg) correlate well with independent measures of beta cell mass, accounting for 64 to 72 percent of the variation [23,24]. These correlations reliably describe the relationship between the mass of islets transplanted in recipients who have undergone pancreas resection and auto-islet intrahepatic transplantation to the metabolic measures of AIRgluc and AIRarg. (See 'Acute insulin response to glucose' below and 'Acute insulin responses to non-glucose stimuli' below.)

Although these tests provide a better estimate of beta cell mass than fasting blood glucose and oral glucose tolerance tests (OGTTs), methodologies with greater sensitivity are needed. One methodology, positron emission tomography (PET) scanning, is being developed to assess beta cell mass. Results are preliminary, and comparisons with traditional metabolic measurements are necessary. (See "Pancreas and islet transplantation in diabetes mellitus".)

Fasting blood glucose and hemoglobin A1C — Measurement of fasting blood glucose has been the conventional method for screening for diabetes, although it is a very insensitive measure of beta cell mass. More than 70 percent of the beta cell mass can be lost (eg, through partial pancreatectomy [25]) in rats without any change in fasting blood glucose concentrations. In humans undergoing hemipancreatectomy, although most continue to have normal glucose tolerance, fasting blood glucose concentrations rise, and the insulin response to oral glucose is impaired [26]. (See "Screening for type 2 diabetes mellitus".)

Glycated hemoglobin (A1C) is also used for screening and identification of impaired glucose tolerance and diabetes. This method reflects the average 24-hour glucose level for the past 90 days and is not affected by an occasional high glucose level. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'A1C'.)

Oral glucose tolerance test — Measurements of blood glucose at specified times after the ingestion of glucose have been widely used in epidemiologic studies to assess the adequacy of insulin secretion and to define the presence or absence of diabetes or impairment of glucose tolerance (see "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults"). However, OGTTs are time consuming and less reproducible than fasting plasma glucose measurements. Nonetheless, a two-hour glucose on the OGTT can still be used to diagnose impaired glucose tolerance. In addition, the OGTT is still used to screen for gestational diabetes. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention".)

Fasting serum insulin — The fasting serum insulin concentration provides information about the subject's insulin sensitivity, but not about reductions in either beta cell mass or function. Serum insulin and blood glucose must be measured at the same time to evaluate insulin secretion properly. As an example, many patients with type 2 diabetes have higher fasting serum insulin concentrations than individuals without diabetes, suggesting that they are oversecreting insulin. However, when the blood glucose concentration in the control subject is raised to that of the patient with type 2 diabetes, the serum insulin concentration is much higher than in the patient with diabetes. The degree of insulin resistance also needs to be considered; obese subjects with normal fasting blood glucose concentrations have fasting serum insulin concentrations several times higher than lean subjects with similar blood glucose concentrations. (See "Insulin resistance: Definition and clinical spectrum".)

Intravenous glucose tolerance test — Rapid intravenous injection of glucose results in a rapid rise in blood glucose concentrations to a peak in three to five minutes, followed by an exponential fall to normal. The rate of decrease between 10 and 30 minutes after the injection can be used to define the glucose disappearance constant, which is an index of glucose tolerance.

Acute insulin response to glucose — The amount of insulin released in the first 10 minutes after intravenous glucose administration (first phase or AIRgluc) is independent of the pre-stimulus blood glucose concentration if it is <100 mg/dL (5.6 mmol/L) and thereby allows comparison of insulin responses between subjects or in the same subject over time without having to match basal blood glucose concentrations before glucose is given [18]. This is a fairly simple test that can be used to help define the risk for type 1 diabetes in susceptible subjects. (See "Type 1 diabetes mellitus: Disease prediction and screening".)

Acute insulin responses to non-glucose stimuli — As previously mentioned, the magnitude of the acute insulin response to amino acids, neurotransmitters, and gut hormones is dependent upon the pre-stimulus blood glucose concentrations. Measurements of the AIRarg, the slope of glucose potentiation of insulin secretion, and the maximum serum insulin response are useful and sensitive measures of beta cell dysfunction in patients with several disease states. As an example, a hallmark of type 2 diabetes is that patients with fasting glucose levels >115 mg/dL (6.4 mmol/L) who do not have a first-phase insulin response to intravenous glucose retain the first-phase response to nonglucose stimuli, such as isoproterenol and arginine (figure 6) [27].

In addition, the blood glucose concentration at which insulin secretion is half maximal is a measure of the sensitivity of an individual's beta cells to the potentiating effects of glucose [22]. These studies require physiologic glucose clamp studies lasting several hours. Thus, these are used mostly in research studies to define the beta cell dysfunction associated with experimental and pathologic conditions.

Insulin sensitivity — The sensitivity or resistance to the actions of insulin varies widely among different subjects, even those with normal glucose metabolism (see "Insulin resistance: Definition and clinical spectrum"). Interpretation of insulin secretion is much more meaningful if it is done in relation to insulin sensitivity. This can be performed by euglycemic glucose clamp studies or by a minimal modeling technique using frequent measurements of blood glucose after intravenous glucose administration (figure 7) [28].

SUMMARY

●Insulin is a peptide hormone composed of 51 amino acids that is synthesized, packaged, and secreted by pancreatic beta cells. Pancreatic beta cells are found in the islets of Langerhans and are surrounded by alpha cells that secrete glucagon, smaller numbers of delta cells that secrete somatostatin, and PP cells that secrete pancreatic polypeptide (figure 1). (See 'Anatomy' above.)

●Insulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum. Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus, where it is packaged into secretory granules located close to the cell membrane. Proinsulin is cleaved into equimolar amounts of insulin and C-peptide in the secretory granules (figure 2). (See 'Insulin synthesis and secretion' above.)

●The primary regulator of insulin secretion is glucose. Rapid increases in blood glucose concentration (eg, after bolus intravenous administration of glucose) cause a rapid burst of insulin secretion that peaks within three to five minutes and subsides within 10 minutes (called "first-phase" insulin release) (figure 4). If the blood glucose concentration remains high, then the rise in insulin secretion is sustained (called "second-phase" insulin release). (See 'Insulin response to glucose' above.)

●Although there are several metabolic methods of measuring insulin secretion and estimating beta cell mass, including fasting blood glucose and oral and intravenous glucose tolerance tests, measurements of the acute insulin response to glucose (AIRgluc) and arginine (AIRarg) provide a better estimate of beta cell mass than fasting blood glucose and oral glucose tolerance tests (OGTTs). In human experiments, AIRgluc and AIRarg correlate well with independent measures of beta cell mass by insulin immunofluorescent imaging. (See 'Measures of insulin secretion and beta cell mass' above.)