Summary
New treatment strategies for subjects with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus are being developed. Pilot studies utilising insulin itself have been reported to prevent Type 1 diabetes in subjects likely, by immunogenetic and physiologic criteria, to develop clinically overt disease, while the results of nicoti-namide trials in these subjects remain preliminary. Immunotherapy with cyclosporin A and azathioprine can slow disease progression and may produce long-term remissions when given within two months of onset of clinically overt disease.
In subjects with established disease, familial clustering of diabetic nephropathy may be related to concomitant susceptibility to hypertension and elevated rates of Na/H countertransport. Treatment of hypertension associated with the nephropathy appears to slow renal deterioration. Whether reversal of the metabolic consequences of insulin deficiency or resistance also prevents chronic diabetic complications has not been firmly established. In the presence of a reduced Beta-cell mass, moderate hyperglycaemia may itself contribute to decreased muscle glucose uptake but not glycogen synthesis in Type 1 and Type 2 diabetes. Reversal of chronic hyperglycaemia by pancreas and islet cell transplantation, vanadate, and sulphonylureas are discussed as alternate strategies to insulin treatment in establishing normoglycaemia and furthering our understanding of insulin action and secretion at the cellular level. There remains a need to develop more sensitive biochemical and genetic markers to identify subjects at increased risk for developing chronic diabetic complications.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Castano L, Eisenbarth, GS (1990) Type 1 diabetes: a chronic autoimmune disease of man, mouse and rat. Annu Rev Immunol 8: 647–679
Vardi P, Crisa L, Jackson RA et al. (1991) Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients. Diabetologia 34: 93–102
Baekkeskov S, Warnock G, Christie M, Rajotte RW, Larsen PM, Fey S (1989) Revelation of 64K autoantibodies in IDDM serums by high resolution 2-D gel electrophoresis: unambiguous identification of 64 K target antigen. Diabetes 38: 1133–1141
Gotfredsen CF, Buschard K, Frandsen EK (1985) Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia 28: 933–935
Chase HP, Butler-Simon N, Garg S, McDuffie M, Hoops SL, O'Brien D (1990) A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33: 444–446
Stiller CR, Dupre J, Gent M et al. (1984) Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223:1362–1367
Bougneres PF, Carel JC, Castano C et al. (1988) Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 318: 663–670
Borch-Johnsen K, Andersen PK, Deckert T (1985) The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 28: 590–596
Seaquist ER, Goetz FC, Rich S, Barbosa JJ (1989) Familial clustering of diabetic kidney disease. N Engl J Med 320: 1161–1165
Viberti GC, Keen H, Wiseman MJ (1987) Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Brit Med J 295: 515–517
Carr S, Mbanya JC, Thomas T et al. (1990) Increase in glo-merular filtration rate in patients with insulin-dependent diabetes and elevated erythrocyte sodium-lithium countertransport. N Engl J Med 322: 500–505
Ng LL, Simmons D, Frighi V, Garrido MC, Bomford J, Hockaday TDR (1990) Leucocyte Na+/H+ antiport activity in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia 33: 371–377
Krolewski AS, Canessa M, Warram JH et al. (1988) Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 318: 140–145
Raffel LJ, Vadheim CM, Roth M-P, Klein R, Moss SE, Rotter JI (1991) The 5′ insulin gene polymorphism and the genetics of vascular complications in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34: 680–683
Krolewski A, Tryggvason K, Stanton V, Housman D (1991) Diabetic nephropathy and polymorphism in cDNA of the alpha 1 chain of type IV collagen. J Am Soc Nephrol 2: 634
Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci USA 87: 404–408
Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud Y, Keen H (1982) Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet I: 1430–1432
Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC (1984) Structural-functional relationships in diabetic nephropathy. J Clin Invest 74: 1143–1155
Mogensen CE (1992) Angiotensin converting enzyme inhibitors and diabetic nephropathy. Brit Med J 304: 327–328
Cooper ME, Allen TJ, O'Brien RC et al. (1990) Nephropathy in model combining genetic hypertension with experimental diabetes: enalapril versus hydralazine and metoprolol therapy. Diabetes 39: 1575–1579
Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM (1986) Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77: 1925–1930
Sutherland DER, Gruessner A, Mondry-Munns K (1992) Report on results of pancreas transplantation in the United States October 1987 to October 1991 from the United Network for Organ Sharing Registry. In: Terasaki PI (ed) Clinical transplants. UCLA Tissue Typing Laboratory, Los Angeles, pp 31–38
Robertson RP (1991) Pancreas transplantation in humans with diabetes mellitus. Diabetes 40: 1085–1089
Sibley, RK, Sutherland DER, Goetz F, Michael AF (1985) Recurrent diabetes mellitus in the pancreas iso- and allograft. Lab Invest 53: 132–144
Diem P, Redmon JB, Abid M et al. (1990) Glucagon, catecholamine and pancreatic polypeptide secretion in type 1 diabetic recipients of pancreas allografts. J Clin Invest 86: 2008–2013
Diem P, Abid M, Redmon JB, Sutherland DER, Robertson RP (1990) Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type 1 diabetic recipients. Diabetes 39: 534–540
Ramsay RC, Goetz FC, Sutherland DER et al. (1988) Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 318: 208–214
Bilous RW, Mauer SM, Sutherland DER, Najarian JS, Goetz FC, Steffes MW (1989) The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med 321: 80–85
Kennedy WR, Navarro X, Goetz FC, Sutherland DER, Najarian JS (1990) Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 322: 1031–1037
Navarro X, Kennedy WR, Loewenson RB, Sutherland DER (1990) Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabetes 39: 802–806
Farney AC, Najarian JS, Nakhleh RE et al. (1991) Autotransplant of dispersed pancreatic islet tissue combined with total or near total pancreatectomy for treatment of chronic pancreatitis. Surgery 110: 427–437
Alejandro R, Latif Z, Polonsky KS, Shienvold FL, Civantos F, Mintz DH (1988) Natural history of multiple intrahepatic canine islet allografts during and following administration of cyclosporine. Transplantation 45: 1036–1041
Ricordi C, Tzakis AG, Carroll PB (1992) Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation 53: 407–414
Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV (1992) Long-term follow-up after transplantation of insulin- producing pancreatic islets into patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35: 89–95
Shechter Y (1990) Perspective in diabetes: insulin-mimetic effects of vanadate; possible implications for future treatment of diabetes. Diabetes 39: 1–5
Helliger CE, Tahiliani AG, McNeill JH (1985) Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1476
Gil J, Mirapelx M, Carreras J, Bartrons R (1988) Insulin-like effects of vanadate on glucokinase activity and fructose 2,6- bisphosphate levels in the liver of diabetic rats. J Biol Chem 263: 1868–1871
Strout HV, Vacario PP, Biswas C et al. (1990) Vanadate treatment of streptozotocin diabetic rats restores expression of the insulin-responsive glucose transporter in skeletal muscle. Endocrinology 126: 2728–2732
Rossetti L, Laughlin MR (1989) Correction of chronic hyperglycaemia with vanadate, but not with phlorizin, normalises in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. J Clin Invest 84: 892–899
Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir SA, Kahn CR (1991) Vanadate normalises hyperglycaemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest 87: 1286–1294
Boyd AEI (1988) Sulfonylurea receptors, ion channels, and fruit flies. Diabetes 37: 847–850
Rossetti L, Giaccair A (1990) Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake: a dose-response euglycaemic clamp study in normal and diabetic rats. J Clin Invest 85: 1785–1792
Rossetti L, Shulman GI, Zawalich W, DeFronzo RA (1987) Effect of chronic hyperglycaemia on in vivo insulin secretion in partially pancreatectomised rats. J Clin Invest 80: 1037–1044
Leahy JL, Bonner-Weir S, Weir GC (1988) Minimal chronic hyperglycaemia is a critical determinant of impaired insulin secretion after incomplete pancreatectomy. J Clin Invest 81: 1407–1414
Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA (1987) Correction of hyperglycaemia with phlorizin normalises tissue sensitivity to insulin in diabetic rats. J Clin Invest 79: 1510–1515
Kahn BB, Shulman GI, DeFronzo RA, Cushman SW, Rossetti L (1991) Normalisation of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J Clin Invest 87: 561–570
Richter EA, Hansen BF, Hansen SA (1988) Glucose-induced insulin resistance of skeletal muscle glucose transport and uptake. Biochem J 252: 733–737
Garvey WT, Olefsky JM, Matthaei S, Marshall S (1987) Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. J Biol Chem 262: 189–197
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Robertson, R.P., Klein, D.J. Treatment of diabetes mellitus. Diabetologia 35 (Suppl 2), S8–S17 (1992). https://doi.org/10.1007/BF00586274
Issue Date:
DOI: https://doi.org/10.1007/BF00586274