Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible?

Cerasi, Erol

doi:10.1007/bf00400591

Cited by 72 publications

(32 citation statements)

References 51 publications

(46 reference statements)

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“…However, if glucose sensitivity is impaired, total insulin secretion is not sufficient to cope with the increased insulin demand and hyperglycaemia ensues. This results from the coexistence of insulin resistance with an intrinsic defect in beta cell glucose sensing on a background of normal coupling between IS and the fasting secretory tone [23]. Clearly, deterioration of the glucose sensing defect over time is likely to be a further contributor to hyperglycaemia [10], possibly sustained by glucotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

Mari¹,

Tura²,

Natali

et al. 2010

Diabetologia

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Aims/hypothesis It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose. Methods In men and women with NGT (n=1,123) or IGR (n=156) (age 44±8 years, BMI 25±4 kg/m 2 , mean ± SD) we measured: (1) IS by clamp; (2) insulin secretion rates (ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose. Results After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups, whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. In IGR vs NGT, IS was impaired (92 [75] , p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p< 0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels. Conclusions/interpretation Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

Mari¹,

Tura²,

Natali

et al. 2010

Diabetologia

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“…The 30-year controversy on whether type 2 diabetes is a disorder of reduced insulin action or diminished insulin secretion is abating, with most investigators accepting that diminished insulin secretion is a necessary condition for the development of impaired glucose homeostasis [3,[16][17][18]. The main reason for underestimating the deficit in insulin secretion is failure to recognise the modulating effect of insulin sensitivity on beta cell function [14].…”

Section: Discussionmentioning

confidence: 99%

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years

et al. 2005

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Aims/hypothesis: Insulin resistance and insulin deficiency are proposed as risk factors for IGT and type 2 diabetes. We assessed the predictive value of initial parameters for the outcome of an OGTT performed 24.3±2.9 years later in an unselected healthy non-obese population. Methods: The K-value of an IVGTT was determined in 267 healthy subjects (mean±SD: age 31.0±12.0 years, BMI 21.8±2.8 kg/m 2 ). First-phase insulin response to a glucose infusion test was estimated as an incremental 5-or 10-min (ΔI5 or ΔI10) value, and as insulinogenic indices (ΔI5/ΔG5 or ΔI10/ΔG10) adjusted for insulin sensitivity determined by homeostasis model assessment for insulin resistance ([ΔI5/ΔG5]/HOMA-IR). Results: At followup, six subjects had type 2 diabetes and 47 had IGT; 214 retained normal glucose tolerance. Insulin sensitivity and early (30 min) insulin response decreased with decreasing outcome OGTT. Blood glucose (2 h) at OGTT correlated positively with initial age and BMI, and negatively with ΔI5/ΔG5, (ΔI5/ΔG5)/HOMA-IR and K-value. In multiple linear regression analysis, (ΔI5/ΔG5)/HOMA-IR, ΔI10, K-value, age, HOMA estimate of insulin secretion, and fasting plasma glucose were significantly associated with 2-h OGTT blood glucose. Similar results were obtained on comparing differences between subjects with normal and decreased (IGT+diabetes) glucose tolerance. Conclusions/interpretation: In 267 non-obese healthy subjects, initial K-value and first-phase insulin response to glucose adjusted for insulin sensitivity, but not insulin sensitivity itself, were strong predictors of the outcome of an OGTT performed 25 years later. Thus, in contrast to obese or other high-risk populations, in lean subjects, decreased beta cell function, but not insulin resistance itself, determines future glucose tolerance.

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“…Several authors have suggested that diabetes is characterised by insufficient beta cell adaptation to insulin resistance [15,21,22] followed by beta cell failure. While there is increasing evidence suggesting that glucose plays a critical role in beta cell failure [23,24,25,26,27], the role of glucose during the early phase of insufficient adaptation has been the subject of much debate.…”

Section: Discussionmentioning

confidence: 99%

Metabolic adaptations to chronic glucose infusion in rats

2004

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Aims/hypothesis. Several studies have employed the chronic glucose infusion protocol to quantify the metabolic adaptations associated with a prolonged glucose challenge. However, the limited number of indices and time points reported by these studies has generated an incomplete picture of this process. In this study we aimed to generate an integrative and dynamic picture of the physiological adaptations that occur during chronic glucose infusion. Methods. Sprague-Dawley rats were infused with either 50% dextrose or saline (2 ml/h) for a period of between 0 and 6 days. Glucose, insulin and NEFA dynamics were determined from daily blood samples. Subsets of animals were killed daily for histological determination of beta cell mass, size and replication rates. The mathematical model of coupled beta cell mass, insulin and glucose (the βIG model) was used to estimate insulin sensitivity, beta cell function and net neogenesis from this data. Results. Glucose-infused rats displayed transient hyperglycaemia, persistent hyperinsulinaemia and unchanged NEFA levels. Insulin sensitivity decreased by approximately 80% during the first day of glucose infusion, but had returned to pre-infusion levels by Day 3. Beta cell function was four to six times higher than in control rats throughout the experiment. Beta cell mass doubled over the 6 days of glucose infusion due to three phases of adaptation: (i) neogenesis; (ii) hypertrophy and hyperplasia; and (iii) continued hyperplasia coupled to a second wave of neogenesis. Conclusions/interpretation. Contrary to the results reported for perfused pancreas and in vitro experiments, we found that chronic glucose infusion elevated beta cell function. The prediction of a second wave of beta cell neogenesis, coupled with our previous report of "focal areas" on Day 3, suggests the existence of delayed acinar-to-islet transdifferentiation.

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Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible?

Cited by 72 publications

References 51 publications

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years

Metabolic adaptations to chronic glucose infusion in rats

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