Insulin secretion and pancreatic beta cell function
- R Paul Robertson, MD
R Paul Robertson, MD
- Pacific Northwest Research Diabetes Institute
- Professor of Medicine and Pharmacology
- University of Washington
- University of Minnesota
- Section Editors
- Irl B Hirsch, MD
Irl B Hirsch, MD
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- University of Washington School of Medicine
- Joseph I Wolfsdorf, MB, BCh
Joseph I Wolfsdorf, MB, BCh
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Harvard Medical School
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 function of the insulin receptor after binding insulin and the mechanisms of insulin action are discussed separately. (See "Structure and function of the insulin receptor" and "Insulin action".)
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 about 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 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.
- Goodner CJ, Walike BC, Koerker DJ, et al. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science 1977; 195:177.
- Bingley PJ, Matthews DR, Williams AJ, et al. Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects. Diabetologia 1992; 35:32.
- Yasuda K, Yamada Y, Inagaki N, et al. Expression of GLUT1 and GLUT2 glucose transporter isoforms in rat islets of Langerhans and their regulation by glucose. Diabetes 1992; 41:76.
- Liang Y, Cushman SM, Whitesell RR, Matschinsky FM. GLUT1 is adequate for glucose uptake in GLUT2-deficient insulin-releasing beta-cells. Horm Metab Res 1997; 29:255.
- Matschinsky F, Liang Y, Kesavan P, et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest 1993; 92:2092.
- Matschinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996; 45:223.
- Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 1993; 328:697.
- Grupe A, Hultgren B, Ryan A, et al. Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Cell 1995; 83:69.
- Terauchi Y, Sakura H, Yasuda K, et al. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem 1995; 270:30253.
- Koster JC, Marshall BA, Ensor N, et al. Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 2000; 100:645.
- Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268:423.
- Sperling MA, Menon RK. Hyperinsulinemic hypoglycemia of infancy. Recent insights into ATP-sensitive potassium channels, sulfonylurea receptors, molecular mechanisms, and treatment. Endocrinol Metab Clin North Am 1999; 28:695.
- Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355:467.
- Babenko AP, Polak M, Cavé H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355:456.
- Kulkarni RN, Brüning JC, Winnay JN, et al. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96:329.
- Ferrannini E, Pilo A. Pattern of insulin delivery after intravenous glucose injection in man and its relation to plasma glucose disappearance. J Clin Invest 1979; 64:243.
- McCulloch DK, Bingley PJ, Colman PG, et al. Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study. Diabetes Care 1993; 16:911.
- Brunzell JD, Robertson RP, Lerner RL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 1976; 42:222.
- Hollander PM, Asplin CM, Palmer JP. Glucose modulation of insulin and glucagon secretion in nondiabetic and diabetic man. Diabetes 1982; 31:489.
- Ward WK, Bolgiano DC, McKnight B, et al. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest 1984; 74:1318.
- Robertson RP. Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes 2007; 56:2420.
- Robertson RP, Bogachus LD, Oseid E, et al. Assessment of β-cell mass and α- and β-cell survival and function by arginine stimulation in human autologous islet recipients. Diabetes 2014.
- Bonner-Weir S, Trent DF, Weir GC. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J Clin Invest 1983; 71:1544.
- Kendall DM, Sutherland DE, Najarian JS, et al. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 1990; 322:898.
- Robertson RP, Porte D Jr. The glucose receptor. A defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor. J Clin Invest 1973; 52:870.
- Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev 1985; 6:45.
- INSULIN SYNTHESIS AND SECRETION
- Role of glucose
- - Insulin response to glucose
- MEASURES OF INSULIN SECRETION AND BETA CELL MASS
- Fasting blood glucose and hemoglobin A1C
- Oral glucose tolerance test
- Fasting serum insulin
- Intravenous glucose tolerance test
- Acute serum insulin response to glucose
- Acute serum insulin responses to non-glucose stimuli
- Insulin sensitivity