Summary:
The ability of insulin to stimulate muscle glucose disposal and inhibit adipose tissue
lipolysis is impaired in patients with type 2 diabetes. The progression from normal
glucose tolerance and/or impaired glucose tolerance to type 2 diabetes only occurs
when insulin secretory function declines to a degree that circulating insulin concentrations
are no longer able to overcome muscle and adipose tissue insulin resistance. Although,
ambient plasma insulin concentrations are not sufficiently high to maintain euglycaemia
in patients with type 2 diabetes, absolute plasma insulin concentrations in these
individuals are as high, if not higher, than in nondiabetic subjects. Since the plasma
concentrations of insulin, or free fatty acids (FFAs), or both, are elevated in patients
with type 2 diabetes secondary to muscle and adipose tissue insulin resistance, hypertriglyceridaemia
is common in these individuals. Improvement in glycaemic control with insulin or insulin
secretagogues is achieved by raising plasma insulin concentrations to a level high
enough to overcome the insulin resistance. This is not the case with thiazolidinediones
(TZDs): glycaemic control is associated with lower plasma insulin concentration. Compounds
that improve insulin sensitivity and lead to lower glucose and insulin concentrations
may have unique clinical benefit in the treatment of patients with type 2 diabetes.
Key words:
Insulin resistance - dyslipidaemia - coronary heart disease - thiazolidinediones
References
- 1
Carantoni M, Abbasi F, Chu L, Chen Y D, Reaven G M, Tsao P S, Varasteh B, Cooke J P.
Adherence of mononuclear cells to endothelium in vitro is increased in patients with
NIDDM.
Diabetes Care.
20
1462-1465
1997;
- 2
Carpentier A, Mittelman S D, Lamarche B, Bergman R N, Giacca A, Lewis G F.
Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA
elevation.
Am J Physiol.
39
E1055-E1066
1999;
- 3
Chen N G, Abbasi F, Lamendola C, McLaughlin T, Cooke J P, Tsao P S, Reaven G M.
Mononuclear cell adherence to cultured endothelium is enhanced by hypertension and
insulin resistance in healthy nondiabetic volunteers.
Circulation.
100
940-943
1999a;
- 4
Chen N G, Holmes M, Reaven G M.
Relationship between insulin resistance, soluble adhesion molecules, and mononuclear
cell binding in healthy volunteers.
J Clin Endocrinol Metab.
84
3485-3489
1999b;
- 5
Chen N G, Reaven G M.
Fatty acid inhibition of glucose-stimulated insulin secretion is enhanced in pancreatic
islets from insulin-resistant rats.
Metabolism.
48
1314-1317
1999;
- 6
Chen Y D, Reaven G M.
Insulin resistance and atherosclerosis.
Diabetes Rev.
5
331-342
1997;
- 7
Chen Y D, Swami S, Skowronski R, Coulston A M, Reaven G M.
Effect of variations in dietary fat and carbohydrate intake on postprandial lipemia
in patients with noninsulin dependent diabetes mellitus.
J Clin Endocrinol Metab.
76
347-351
1993;
- 8
Feingold K R, Grunfeld C, Pang M, Doerrler W, Krauss R M.
LDL subclass phenotypes and triglyceride metabolism in non-insulin dependent diabetes.
Arterioscler Thromb Vasc Biol.
12
1496-1502
1992;
- 9
Fonseca V A, Valiquett T R, Huang S M, Ghazzi M N, Whitcomb R W.
Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes
mellitus: A randomized, controlled study. The Troglitazone Study Group.
J Clin Endocrinol Metab.
83
3169-3176
1998;
- 10
Golay A, Zech L, Shi M Z, Chiou Y A, Reaven G M, Chen Y D.
High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus:
Measurement of HDL turnover using tritiated HDL.
J Clin Endocrinol Metab.
65
512-518
1987;
- 11
Jones C N, Pei D, Staris P, Polonsky K S, Chen Y D, Reaven G M.
Alterations in the glucose-stimulated insulin secretory dose-response curve and in
insulin clearance in nondiabetic insulin-resistant individuals.
J Clin Endocrinol Metab.
82
1834-1838
1997;
- 12
Leahy J L, Cooper H E, Deal D A, Weir G C.
Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion.
A study in normal rats using chronic in vivo glucose infusions.
J Clin Invest.
77
908-915
1986;
- 13
Lehto S, Ronnemaa T, Pyorala K, Laakso M.
Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death
from coronary heart disease in patients with type II diabetes.
Diabetologia.
43
148-155
2000;
- 14
Liu G C, Coulston A M, Lardinois C K, Hollenbeck C B, Moore J G, Reaven G M.
Moderate weight loss and sulfonylurea treatment of non-insulin-dependent diabetes
mellitus. Combined effects.
Arch Intern Med.
145
665-669
1985;
- 15
Maggs D G, Buchanan T A, Burant C F, Cline G, Gumbiner B, Hsueh W A, Inzucchi S, Kelley D,
Nolan J, Olefsky J M, Polonsky K S, Silver D, Valiquett T R, Shulman G I.
Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized,
double-blind, placebo-controlled trial.
Ann Intern Med.
128
176-185
1998;
- 16
Meigs J B, Mittleman M A, Nathan D M, Tofler G H, Singer D E, Murphy-Sheehy P M, Lipinska I,
D'Agostino R B, Wilson P W.
Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring
Study.
JAMA.
283
221-228
2000;
- 17
Paolisso G, Gambardella A, Amato L, Tortoriello R, D'Amore A, Varrichio M, D'Onofrio F.
Opposite effects of short and long-term fatty acid infusion on insulin secretion in
healthy subjects.
Diabetologia.
38
1295-1299
1996;
- 18
Pyorala K.
Relationship of glucose tolerance and plasma insulin to the incidence of coronary
heart disease: results from two population studies in Finland.
Diabetes Care.
2
131-141
1979;
- 19
Pyorala K, Pedersen T R, Kjekshus J, Faergeman O, Olsson A G, Thorgeirsson G.
Cholesterol lowering with simvastatin improves prognosis of diabetic patients with
coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival
Study (4S).
Diabetes Care.
20
614-620
1997;
- 20
Raskin P, Rappaport E B, Cole S T, Yan Y, Patwardhan R, Freed M I.
Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients
with type II diabetes.
Diabetologia.
43
278-284
2000;
- 21
Reaven G M.
Pathophysiology of insulin resistance in human disease.
Physiol Rev.
75
473-486
1995a;
- 22
Reaven G M.
The fourth musketeer - from Alexandre Dumas to Claude Bernard.
Diabetologia.
38
3-13
1995b;
- 23
Reaven G M.
Banting lecture 1988. Role of insulin resistance in human disease.
Diabetes.
37
1595-1607
1988;
- 24
Reaven G M, Chen Y D, Hollenbeck C B, Sheu W H, Ostrega D, Polonsky K S.
Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals
with varying degrees of glucose tolerance.
J Clin Endocrinol Metab.
76
44-48
1993;
- 25
Reaven G M, Chen Y D.
Role of insulin in regulation of lipoprotein metabolism in diabetes.
Diabetes Metab Rev.
4
639-652
1988;
- 26
Reaven G M, Hollenbeck C, Jeng C Y, Wu M S, Chen Y D.
Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients
with NIDDM.
Diabetes.
37
1020-1024
1988;
- 27
Reaven G M, Mondon C E.
Effect of in vivo plasma insulin levels on the relationship between perfusate free
fatty acid concentration and triglyceride secretion by perfused rat livers.
Horm Metab Res.
16
230-232
1984;
- 28
Ross R.
The pathogenesis of atherosclerosis - an update.
N Engl J Med.
314
488-500
1986;
- 29
Sacks F M, Pfeffer M A, Moye L A, Rouleau J L, Rutherford J D, Cole T G, Brown L,
Warnica J W, Arnold J M, Wun C C, Davis B R, Braunwald E.
The effect of pravastatin on coronary events after myocardial infarction in patients
with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
N Engl J Med.
335
1001-1009
1996;
- 30
Savage P J, Bennion L J, Flock E V, Nagulesparan M, Mott D, Roth J, Unger R H, Bennett P H.
Diet-induced improvement of abnormalities in insulin and glucagon secretion and in
insulin receptor binding in diabetes mellitus.
J Clin Endocrinol Metab.
48
999-1007
1979;
- 31
Stanik S, Marcus R.
Insulin secretion improves following dietary control of plasma glucose in severely
hyperglycemic obese patients.
Metabolism.
29
346-350
1980;
- 32
UK Prospective Diabetes Study (UKPDS) Group .
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet.
352
837-853
1998;
- 33
Weiland D, Mondon C E, Reaven G M.
Evidence for multiple causality in the development of diabetic hypertriglyceridaemia.
Diabetologia.
18
335-340
1980;
- 34
Yip J, Facchini F S, Reaven G M.
Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease.
J Clin Endocrinol Metab.
83
2773-2776
1998;
- 35
Zavaroni I, Bonini L, Gasparini P, Barilli A L, Zuccarelli A, Dall'Aglio E, Delsignore R,
Reaven G M.
Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes
mellitus, hypertension, and coronary heart disease: the Barilla factory revisited.
Metabolism.
48
989-994
1999;
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