Metabolic Consequences of Prolonged Hyperinsulinemia in Humans: Evidence for Induction of Insulin Insensitivity

Marangou, Andreas G.; Weber, Kathryn M.; Boston, RC; Aitken, P.; Heggie, James; Kirsner, R. L. G.; Best, James D.; Alford, F.

doi:10.2337/diab.35.12.1383

Cited by 85 publications

(27 citation statements)

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“…FSIGTs were performed as previously described with a glucose dose of 300 mg/kg given over 1 min (19). Data analyses were performed by modification of the method of Bergman et al (18) with the simulation and modeling program SAAM (20).…”

Section: Methodsmentioning

confidence: 99%

Fenfluramine Increases Insulin Action in Patients With NIDDM

et al. 1989

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These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a significant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 +/- 1.2 vs. 8.4 +/- 0.89 mM, mean +/- SE, P less than .01) with no significant fall in fasting serum insulin (20 +/- 2 vs. 24 +/- 3 microU/ml) or C-peptide (1.3 +/- 0.2 vs. 1.3 +/- 0.1 nM). During euglycemic-hyperinsulinemic (1 mU.kg-1.min-1) clamp studies there was a significant increase in insulin action from 12.7 +/- 2.3 to 17.3 +/- 1.8 min-1.10(3) microU.ml-1 (P less than .05), although clamp insulin levels were lower after fenfluramine treatment (136 +/- 14 vs. 96 +/- 9 microU/ml, P less than .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 +/- 1.5 vs. 20.1 +/- 2.1 ml.kg-1.min-1, P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Methodsmentioning

confidence: 99%

Fenfluramine Increases Insulin Action in Patients With NIDDM

et al. 1989

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“…Based on data from a 7-yr surveillance, Hansen and Bodkin (67) have implicated a primary defect in (3-cell control or sensitivity, as evidenced by increased insulin release in response to glucose, and a slight and subsequent significant increase in fasting plasma insulin, abnormalities that precede the fasting plasma glucose elevations and the decrease in plasma insulin and insulin response and the development of glucose intolerance. In addition, some studies in humans support the contention that hyperinsulinemia per se can cause insulin resistance (68,69).…”

Section: Hyperinsulinemia-the Teleological Relationship To the Develomentioning

confidence: 92%

Hyperinsulinemia—How Innocent a Bystander?

Zimmet

1993

Diabetes Care

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Hyperinsulinemia is very much in the spotlight. Debate rages as to its significance and role in the etiology not only of NIDDM, but also other morphological and metabolic risk factors for atherosclerotic cardiovascular disease, including upper-body obesity, dyslipidemia, hypertension, and hyperuricemia. Epidemiological data support a key role for hyperinsulinemia in these disorders but it is far from conclusive except for the fact that hyperinsulinemia and insulin resistance may be present many years before the onset of impaired glucose tolerance and NIDDM, and clearly play a role in their etiology. The thrifty genotype hypothesis provides a plausible basis for a better understanding of how hyperinsulinemia and insulin resistance could lead to glucose intolerance and atherosclerotic cardiovascular disease, but the detailed biochemical mechanisms remain elusive. A role for increased sympathetic nervous system activity, resulting from hypothalamic stimulation as a primary event causing hyperinsulinemia, cannot be excluded as a cause of hyperinsulinemia. The current focus on hyperinsulinemia also has resulted in closer examination of the therapy of diabetes and hypertension, emphasizing the need to avoid hyperinsulinemia in both IDDM and NIDDM individuals because of the putative risk of atherosclerotic cardiovascular disease and hypertension. There is still a paucity of epidemiological data to support a role for hyperinsulinemia in the etiology of hypertension. However, clinical practice already is being influenced by the fact that ACE inhibitors have been shown to reduce insulin resistance in clinical research studies. The research reviewed here, particularly that relating to hyperinsulinemia, insulin resistance, and cardiovascular disease risk factors, has opened new vistas for the treatment and prevention of NIDDM and atherosclerotic cardiovascular disease. Appropriate exercise clearly is associated with improved insulin sensitivity, modification of CVD risk factors, and lower prevalence of NIDDM. Upper-body obesity, the latest culprit in the field, can also be reduced by exercise. Hyperinsulinemia and insulin resistance can be detected in children, adolescents, and young adults. NIDDM can be prevented, but clearly, intervention needs to commence in childhood, and intensive risk factor intervention in subjects with NIDDM can reduce the risk of atherosclerotic cardiovascular disease. It seems paradoxical that prevention of NIDDM and atherosclerotic cardiovascular disease are now possible even though the biochemical and molecular basis of these disorders is not fully understood.

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“…Thus, PI turnover may have not only an acute effect on release but may also play a long-term modulatory role in stimulus-secretion response coupling. From a clinical perspective, the involvement of PI turnover may assume added importance, because hyperinsulinemia may result in an acquired deficit-insulin resistance (41). The contribution of changing patterns of PI turnover to the initiation and persistence of hyperinsulinemia is an issue with important clinical overtones.…”

Section: Fig 3 Fractional 3 H Efflux Rates In Response To Glucose Smentioning

confidence: 99%

Modulation of Insulin Secretion From β-Cells by Phosphoinositide-Derived Second-Messenger Molecules

Zawalich

1988

Diabetes

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In isolated islets, the hydrolysis of membrane phosphoinositides (PI) participates in the transduction of both extracellular and intracellular signals into an effective insulin secretory response. A wide variety of potential second-messenger molecules are generated during the phospholipase C-mediated cleavage of these strategically situated membrane phospholipids. Several distinct but interrelated issues are addressed in this perspective. These include 1) methodological approaches utilized to assess PI turnover, 2) the synergistic relationship between PI-derived second messengers and cAMP, 3) the contribution of changing PI turnover rates to the biphasic pattern of insulin output induced by 20 mM glucose, and 4) the role played by PI turnover in the phenomenon of "memory" displayed by islets after prior stimulation with various agonists. The concept that events unique to PI turnover contribute to beta-cell activation is well founded. Because of uncertainty regarding the exact nature of all PI-derived messengers, however, it is not yet possible to mold the available information into a comprehensive theory of beta-cell activation. Future studies will have to address various important unresolved issues.

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Metabolic Consequences of Prolonged Hyperinsulinemia in Humans: Evidence for Induction of Insulin Insensitivity

Cited by 85 publications

References 0 publications

Fenfluramine Increases Insulin Action in Patients With NIDDM

Fenfluramine Increases Insulin Action in Patients With NIDDM

Hyperinsulinemia—How Innocent a Bystander?

Modulation of Insulin Secretion From β-Cells by Phosphoinositide-Derived Second-Messenger Molecules

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