Impaired β-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance

Chang, Annette M.; Smith, Mindy A; Gałecki, Andrzej T.; Bloem, Cathie J.; Halter, Jeffrey B.

doi:10.1210/jc.2006-0913

Cited by 92 publications

(61 citation statements)

References 28 publications

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“…In the report by Gautier et al [20], the participants at increased risk of diabetes had impaired glucose sensitivity in spite of a similar fasting secretory tone. In addition, in a more recent study employing the graded glucose infusion test in young healthy participants [21], the induction of insulin resistance by administration of nicotinic acid produced an increase in fasting insulin secretion without changing the relationship between insulin secretion and glucose concentration.…”

Section: Discussionmentioning

confidence: 96%

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

101

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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: 96%

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

101

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“…In humans, as shown in Fig. 2, the insulin secretion rate in response to glucose was significantly and progressively decreased in older individuals, with the greatest impairment in older individuals with impaired glucose tolerance compared with older individuals with normal glucose tolerance or with younger individuals matched for degree of insulin resistance (9). In fact, a 50% reduction in b-cell secretory capacity has been observed in older men compared with younger men in response to arginine stimulation (29).…”

Section: Effects Of Agingmentioning

confidence: 87%

The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations

2017

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Nearly a quarter of older adults in the U.S. have type 2 diabetes, and this population is continuing to increase with the aging of the population. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. The usual defects contributing to type 2 diabetes are further complicated by the natural physiological changes associated with aging as well as the comorbidities and functional impairments that are often present in older people. This paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.Diabetes is one of the leading chronic medical conditions among older adults, with high risk for vascular comorbidities such as coronary artery disease, physical and cognitive function impairment, and mortality. Despite decades of effort to prevent diabetes, diabetes remains an epidemic condition with particularly high morbidity affecting older adults. In fact, nearly 11 million people in the U.S. aged 65 years or older (more than 26% of adults aged 65 years or older) meet current American Diabetes Association criteria for diabetes (diagnosed and undiagnosed), accounting for more than 37% of the adult population with diabetes (1). At the same time, adults 65 years or older are developing diabetes at a rate nearly three-times higher than younger adults: 11.5 per 1,000 people compared with 3.6 per 1,000 people among adults aged 20-44 years old (1). However, increasing research in diabetes and aging has improved our understanding of the pathophysiology of diabetes and its association with aging and led to the development of a number of antihyperglycemic medications. The mechanism of diabetes complications has been previously reviewed (2). The current paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population. PATHOPHYSIOLOGY OF TYPE 2 DIABETESType 2 diabetes is by far the most prevalent form of diabetes in older adults and is an age-related disorder. The criteria for diagnosing diabetes are the same for all age groups because the risks of diabetes-related complications are associated with hyperglycemia over time across all age groups (3). Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. These factors contribute to hyperglycemia through effects on both b-cell insulin secretory capacity and on tissue sensitivity to insulin. The occurrence of type 2 diabetes in an older person is complicated by the comorbidities and functional impairments associated with aging.Hyperglycemia develops in type 2 diabetes when there is an imbalance of glucose production (i.e., hepatic glucose production during fasting) and glucose intake (i.e.,

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“…46,[49][50][51][52][53][54][55] Our recent studies have shown that there is a strong lag-correlation between the prevalence of obesity and diabetes in the US population and the increased per capita consumption of niacin, which was attributed primarily to the consumption of fortified grains. 34,35 The toxic effects of niacin may involve a variety of mechanisms, including methyl depletion, changes in NAD-dependent reactions and excessive ROS generation.…”

Section: Arsenicmentioning

confidence: 99%

Dietary methyl-consuming compounds and metabolic syndrome

Zhou

et al. 2011

Hypertens Res

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The metabolic syndrome, a major risk factor for type 2 diabetes and cardiovascular disease, is a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia. Although systemic oxidative stress and aberrant methylation status are known to have important roles in the development of metabolic syndrome, how they occur remains unclear. The metabolism of methyl-consuming compounds generates reactive oxygen species and consumes labile methyl groups; therefore, a chronic increase in the levels of methyl-consuming compounds in the body can induce not only oxidative stress and subsequent tissue injury, but also methyl-group pool depletion and subsequent aberrant methylation status. In the past few decades, the intake amount of methyl-consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption. Thus, increased methyl consumers might have a causal role in the development and prevalence of metabolic syndrome and its related diseases. Moreover, factors that decrease the elimination/ metabolism of methyl-consuming compounds and other xenobiotics (for example, sweat gland inactivity and decreased liver function) or increase the generation of endogenous methyl-consuming compounds (for example, mental stress-induced increase in catecholamine release) may accelerate the progression of metabolic syndrome. Based on current nutrition knowledge and the available evidence from epidemiological, ecological, clinical and laboratory studies on metabolic syndrome and its related diseases, this review outlines the relationship between methyl supply-consumption imbalance and metabolic syndrome, and proposes a novel mechanism for the pathogenesis and prevalence of metabolic syndrome and its related diseases.

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Impaired β-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance

Abstract: Human aging is associated with impaired beta-cell sensitivity to glucose and impaired beta-cell compensation to insulin resistance.

Cited by 92 publications

References 28 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

The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations

Dietary methyl-consuming compounds and metabolic syndrome

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