β-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities

doi:10.1016/S0002-9343(02)01276-7

The American Journal of Medicine

Volume 113, Issue 6, Supplement, 28 October 2002, Pages 3-11

https://doi.org/10.1016/S0002-9343(02)01276-7 Get rights and content

Abstract

Defects in insulin action and insulin secretion are both present in type 2 diabetes, and both are believed to be genetically predetermined. In the absence of a defect in β-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations such as the Pima Indians of Arizona. However, loss of β-cell function leads eventually to the postprandial and fasting hyperglycemia that characterizes type 2 diabetes. This progression occurs despite initially effective antidiabetic therapies, a situation clearly demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS). External factors (access to high-calorie foods, lack of exercise, weight gain), the increased insulin requirements imposed by insulin resistance, and toxicities from hyperglycemia and elevated free fatty acids may all contribute to β-cell deterioration. Free fatty acids, resistin, and tumor necrosis factor (TNF)–α potentially worsen the insulin resistance. β-Cell dysfunction resulting from glucose toxicity and lipotoxicity is potentially reversible with restoration of metabolic control. Therefore, attention to these toxicities may delay the deterioration of β-cell function and suggest new approaches to the management of type 2 diabetes.

Section snippets

Natural history of type 2 diabetes

As depicted in Figure 1, ⁸ the classic pathogenesis of type 2 diabetes involves insulin resistance, marked by compensatory hyperinsulinemia, and β-cell dysfunction, marked by declining insulin secretion and worsening hyperglycemia. In this figure, Year 0 represents the onset of diabetes; note, however, that significant insulin resistance may exist for a decade or more before this onset.

The progression from these metabolic impairments to a disease state does not hinge on insulin resistance. To

Relation and progression of diabetic defects

The nature of the relation between insulin resistance and insulin secretion is important given the role of this relation in disease progression, as well as the fact that modern antidiabetic therapies aim to regulate it. Kahn and coworkers⁹ plotted the relation in healthy volunteers with varying degrees of obesity and found a hyperbolic curve linking insulin sensitivity and β-cell function (Figure 2). That is, the patients’ insulin responses varied in quantity according to differences in their

Impact of treatment on disease progression

The crucial question in the minds of clinicians is whether current forms of therapy can affect the decline in β-cell function in type 2 diabetes. The most informative data on this question come from the United Kingdom Prospective Diabetes Study (UKPDS),¹³ which, like many studies, had the goal of understanding how to reduce long-term complications in patients with established diabetes. Patients in the UKPDS were randomized to either conventional therapy with diet and exercise or pharmacologic

physiology and defects of insulin secretion

β-Cells are responsible for maintaining a narrow range of blood glucose levels. The cells work in a feedback loop with glucose, as follows: hyperglycemia signals the β-cells to produce insulin and suppress glucagon, which switches off glucose production from the liver and increases glucose uptake in muscle, fat, and liver; hypoglycemia signals the β-cells to decrease insulin secretion and increase glucagon, which stimulates glucose production from the liver. Fatty acids and amino acids

Physiology and defects of insulin action

Insulin resistance may best be described as the loss of insulin regulation by the normal amount of insulin—that is, a condition of reduced insulin sensitivity.² Insulin stimulates glucose uptake chiefly in skeletal and myocardial muscle and adipocytes. It also augments the ability of hyperglycemia to promote hepatic glucose uptake through its effects on intracellular enzymes, but in contrast to its effects on peripheral insulin-target tissues, it has no direct effect on hepatic glucose

Toxicities of the internal environment

Chronically elevated levels of glucose and fatty acids create an environment that may further threaten the function of β-cells and the action of insulin. Unlike genetic defects, these problems may be temporary and reversible if the metabolic derangements themselves can be corrected (insulin therapy in particular has been recommended for this task).24, 31 Nevertheless, the toxicities are complex and intertwined in ways that make correction challenging.

Conclusions

Type 2 diabetes is associated with both insulin resistance and impaired insulin secretion, each of which is believed to be genetically predetermined. The natural history of the disease is one of progression, characterized by declining ability to control hyperglycemia with endogenous insulin secretion. This difficulty in maintaining normal glucose has been attributed to the deterioration of β-cell function; indeed, such deterioration is a prerequisite to a disease state, because many patients

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Glucose homeostasis is primarily maintained by an endocrine hormone, insulin, which is secreted by pancreatic β-cells. Insulin enhances glucose storage or regulates glycogen breakdown in muscle cells, keeping the blood glucose level within a controlled range (LeRoith, 2002). When the β-cells produce an insufficient amount of insulin or when the body cannot use the insulin properly, it leads to high blood glucose levels or hyperglycemia, which is the hallmark of diabetes mellitus (Ashcroft and Rorsman, 2012; Porte and Kahn, 2001).
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^☆: Derek LeRoith, MD, received speaking fees from Pfizer, Inc., Aventis Pharmaceuticals, Inc., Takeda, and Bristol-Myers Squibb, Co.

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Original articleβ-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities☆

Abstract

Section snippets

Natural history of type 2 diabetes

Relation and progression of diabetic defects

Impact of treatment on disease progression

physiology and defects of insulin secretion

Physiology and defects of insulin action

Toxicities of the internal environment

Conclusions

Endocrinol Metab Clin North Am

Diabetes Res Clin Pract

J Diabetes Complications

Endocr Pract

Atherosclerosis

The genetic basis of type 2 diabetes mellitusimpaired insulin secretion versus impaired insulin sensitivity

Endocr Rev

Pathogenesis of type 2 diabetes

Drug Benefit Trends

Type 2 diabetesan overview

Clin Chem

Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellituserrors of metabolism or of methods?

Diabetologia

Fatty acids and insulin resistance

Diabetes Care

Management of type 2 diabetesa systemic approach to meeting standards of care. II. Oral agents, insulin and management of complications

Quantification of the relationship between insulin sensitivity and β-cell function in human subjectsevidence for a hyperbolic function

Diabetes

The importance of the β-cell in the pathogenesis of type 2 diabetes mellitus

Am J Med

Diabetes mellitus in the Pima Indiansincidence, risk factors and pathogenesis

Diabetes Metab Rev

The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus

J Clin Invest

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

U.K. prospective diabetes study 16overview of 6 years’ therapy of type II diabetes: a progressive disease

Diabetes

Homeostasis model assessmentinsulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man

Diabetologia

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

Lancet

Effect of troglitazone on insulin sensitivity and pancreatic beta-cell function in women at high risk for NIDDM

Diabetes

The key role of islet dysfunction in type II diabetes mellitus

Clin Invest Med

β-Cells in type II diabetes mellitus

Diabetes

Triggering and amplifying pathways of regulation of insulin secretion by glucose

Diabetes

Original article
β-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities☆