Attenuation of Endocrine-Exocrine Pancreatic Communication in Type 2 Diabetes: Pancreatic Extracellular Matrix Ultrastructural Abnormalities
Melvin R. Hayden MD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
Search for more papers by this authorJavad Habibi PhD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Search for more papers by this authorAdam Whaley-Connell DO, MSPH
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Search for more papers by this authorJames R. Sowers MD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Department of Physiology and Pharmacology, University of Missouri-Columbia School of Medicine, Columbia, MO
Search for more papers by this authorMelvin R. Hayden MD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
Search for more papers by this authorJavad Habibi PhD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Search for more papers by this authorAdam Whaley-Connell DO, MSPH
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Search for more papers by this authorJames R. Sowers MD
From the Department of Internal Medicine
Diabetes Cardiovascular Center
The Harry S. Truman VA Medical Center
Department of Physiology and Pharmacology, University of Missouri-Columbia School of Medicine, Columbia, MO
Search for more papers by this authorAbstract
Ultrastructural observations reveal a continuous interstitial matrix connection between the endocrine and exocrine pancreas, which is lost due to fibrosis in rodent models and humans with type 2 diabetes mellitus (T2DM). Widening of the islet-exocrine interface appears to result in loss of desmosomes and adherens junctions between islet and acinar cells and is associated with hypercellularity consisting of pericytes and inflammatory cells in T2DM pancreatic tissue. Organized fibrillar collagen was closely associated with pericytes, which are known to differentiate into myofibroblasts—pancreatic stellate cells. Of importance, some pericyte cellular processes traverse both the connecting islet-exocrine interface and the endoacinar interstitium of the exocrine pancreas. Loss of cellular paracrine communication and extracellular matrix remodeling fibrosis in young animal models and humans may result in a dysfunctional insulino-acinar-ductal–incretin gut hormone axis, resulting in pancreatic insufficiency and glucagon-like peptide deficiency, which are known to exist in prediabetes and overt T2DM in humans.
References
- 1 Pieler T, Chen Y. Forgotten and novel aspects in pancreas development. Biol Cell. 2006; 98(2): 79–88.
- 2 Bertelli E, Bendayan M. Association between endocrine pancreas and ductal system. More than an epiphenomenon of endocrine differentiation and development? J Histochem Cytochem. 2005; 53: 1071–1086.
- 3 Hayden MR, Karuparthi PR, Habibi J, et al. Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP. 2007; 8(6): 725–738.
- 4 Habibi J, Whaley-Connell A, Hayden MR, et al. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Endocrinology. 2008; 149(11): 5643–5653.
- 5 Hayden MR, Karuparthi PR, Manrique CM, et al. Longitudinal ultrastructure study of islet amyloid in the HIP rat model of type 2 diabetes mellitus. Exp Biol Med (Maywood). 2007; 232(6): 772–779.
- 6 Neubauer N, Kulkarni RN. Molecular approaches to study control of glucose homeostasis. ILAR J. 2006; 47(3): 199–211.
- 7 Zhou YP, Madjidi A, Wilson ME, et al. Matrix metalloproteinases contribute to insulin insufficiency in Zucker diabetic fatty rats. Diabetes. 2005; 54(9): 2612–2619.
- 8 Hayden MR, Stump CS, Sowers JR. Introduction: organ involvement in the cardiometabolic syndrome. J Cardiometab Syndr. 2006; 1(1): 16–24.
- 9 Hayden MR, Karuparthi PR, Habibi J, et al. Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes. Exp Biol Med (Maywood). 2008; 233(9): 1109–1123.
- 10 Nakamura M, Kitamura H, Konishi S, et al. The endocrine pancreas of spontaneously diabetic db/db mice: microangiopathy as revealed by transmission electron microscopy. Diabetes Res Clin Pract. 1995; 30(2): 89–100.
- 11 Hayden MR, Whaley-Connell A, Sowers JR. Role of angiotensin II in diabetic cardiovascular and renal disease. Curr Opin Endocrinol Diabetes. 2006; 13: 135–140.
- 12 Shao J, Iwashita N, Ikeda F, et al. Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on beta-cell function and morphology in db/db mice. Biochem Biophys Res Commun. 2006; 344(4): 1224–1233.
- 13 Hayden MR, Sowers JR. Pancreatic renin-angiotensin-aldosterone system in the cardiometabolic syndrome and type 2 diabetes mellitus. J Cardiometab Syndr. 2008; 3(3): 129–131.
- 14 Hayden MR, Sowers JR. Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome. Am J Hypertens. 2008; 2(4): 239–266.
- 15 Clark RA. Cutaneous tissue repair: basic biologic considerations. I. J Am Acad Dermatol. 1985; 13(5 pt 1): 701–725.
- 16 Hayden MR, Sowers JR. Redox imbalance in diabetes. Antioxid Redox Signal. 2007; 9(7): 865–857.
- 17 Hayden MR, Sowers JR. Isletopathy in type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling and oxidative stress. Antioxid Redox Signal. 2007; 9(7): 891–910.
- 18 Zhao HL, Lai FMM, Tong PC, et al. Prevalence and clinicopathological characteristics of islet amyloid in Chinese patients with type 2 diabetes. Diabetes. 2003; 52(11): 2759–2766.
- 19 Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998; 43: 128–133.
- 20 Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998; 115: 421–432.
- 21 Omary MB, Lugea A, Lowe AW, et al. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest. 2007; 117: 50–59.
- 22 Pezzilli R. Pancreatic stellate cells and chronic alcoholic pancreatitis. JOP. 2007; 8: 254–257.
- 23 Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol. 2004; 99(11): 2256–2270.
- 24 Schmitt-Graff A, Kruger S, Bochard F, et al. Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am J Pathol. 1991; 138: 1233–1242.
- 25 Doherty MJ, Ashton BA, Walsh S, et al. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res. 1998; 13: 828–838.
- 26 Ivarsson M, Sundberg C, Farrokhnia N, et al. Recruitment of type I collagen producing cells from the microvasculature in vitro. Exp Cell Res. 1996; 229: 336–349.
- 27 Sundberg C, Ivarsson M, Gerdin B, et al. Pericytes as collagen-producing cells in excessive dermal scarring. Lab Invest. 1996; 74: 452–466.
- 28 Richardson RL, Hausman GJ, Campion DR. Response of pericytes to thermal lesion in the inguinal fat pad of 10-day-old rats. Acta Anat (Basel). 1982; 114: 41–57.
- 29 Hattori M, Horita S, Yoshioka T, et al. Mesangial phenotypic changes associated with cellular lesions in primary focal segmental glomerulosclerosis. Am J Kidney Dis. 1997; 30: 632–638.
- 30 Allt G, Lawrenson JG. Pericytes: cell biology and pathology. Cells Tissues Organs. 2001; 169: 1–11.
- 31 Sims DE. The pericyte. A review. Tissue Cell. 1986; 18: 153–174.
- 32 Shepro D, Morel NM. Pericyte physiology. FASEB J. 1993; 7: 1031–1038.
- 33 Li AF, Sato T, Haimovici R, et al. High glucose alters connexin 43 expression and gap junction intercellular communication activity in retinal pericytes. Invest Ophthalmol Vis Sci. 2003; 44: 5376–5382.
- 34 Yaginuma N, Takahashi T, Saito K, et al. Reconstruction study of the structural plan of the human pancreas. Jpn J Gastroenterol. 1981; 78: 1282–1292.
- 35 Ohtani O. Three-dimensional organization of the connective tissue fibers of the human pancreas: a scanning electron microscopic study of NaOH treated-tissues. Arch Histol Jpn. 1987; 50(5): 557–566.
- 36 Hayden MR. Islet amyloid and fibrosis in cardiometabolic syndrome and type 2 diabetes mellitus. J Cardiometab Syndr. 2007; 2(1): 70–75.
- 37 Laakso M, Zilinskaite J, Hansen T, et al. Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study. Diabetologia. 2008; 51(3): 502–511.
- 38 Knop FK, Vilsbøll T, Højberg PV, et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007; 56(8): 1951–1959.
- 39 Knop FK, Vilsbøll T, Larsen S, et al. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab. 2007; 292(1): E324–E330.
- 40 Creutzfeldt W. The incretin concept today. Diabetologia. 1979; 16: 75–85.
- 41 Elrick H, Stimmler L, Hlad CJ, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24: 1076–1082.
- 42 Nauck M, Stockmann F, Ebert R, et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986; 29(1): 46–52.
- 43 Nauck MA, Heimesaat MM, Orskov C, et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993; 91(1): 301–307.
- 44 Hardt PD, Brendel MD, Kloer HU, et al. Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed? Diabetes Care. 2008; 31(suppl 2): S165–S169.
- 45 Hardt PD. Second Giessen International Workshop on Interactions of Exocrine and Endocrine Pancreatic Diseases. Castle of Rauischholzhausen of the Justus-Liebig-university, Giessen (Rauischholzhausen), Germany. March 7–8, 2008. JOP. 2008; 9(4): 541–575.
- 46 Yilmaztepe A, Ulukaya E, Ersoy C, et al. Investigation of fecal pancreatic elastase-1 levels in type 2 diabetic patients. Turk J Gastroenterol. 2005; 16(2): 75–80.