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Recent Advances in In-Vitro Assays for Type 2 Diabetes Mellitus: An Overview
review-article
Author(s):
Nazmina Vhora
1
,
2 ,
Ujjal Naskar
2
,
3 ,
Aishwarya Hiray
2
,
3 ,
Abhijeet S. Kate
3
,
,
Alok Jain
1
,
4
,
Publication date (Electronic):
01 May 2021
Journal:
The Review of Diabetic Studies : RDS
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Abstract
BACKGROUND
A higher rate of attenuation of molecules in drug discovery has enabled pharmaceutical companies to enhance the efficiency of their hit identification and lead optimization. Selection and development of appropriate invitro and in-vivo strategies may improve this process as primary and secondary screening utilize both strategies. In-vivo approaches are too relentless and expensive for assessing hits. Therefore, it has become indispensable to develop and implement suitable in-vitro screening methods to execute the required activities and meet the respective targets. However, the selection of an appropriate in-vitro assay for specific evaluation of cellular activity is no trivial task. It requires thorough investigation of the various parameters involved.
AIM
In this review, we aim to discuss in-vitro assays for type 2 diabetes (T2D), which have been utilized extensively by researchers over the last five years, including target-based, non-target based, low-throughput, and high-throughput screening assays.
METHODS
The literature search was conducted using databases including Scifinder, PubMed, ScienceDirect, and Google Scholar to find the significant published articles.
DISCUSSION and CONCLUSION
The accuracy and relevance of in-vitro assays have a significant impact on the drug discovery process for T2D, especially in assessing the antidiabetic activity of compounds and identifying the site of effect in high-throughput screening. The report reviews the advantages, limitations, quality parameters, and applications of the probed invitro assays, and compares them with one another to enable the selection of the optimal method for any purpose. The information on these assays will accelerate numerous procedures in the drug development process with consistent quality and accuracy.
Related collections
Most cited references63
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Diagnosis and Classification of Diabetes Mellitus
Vittorio Basevi (2010)
DEFINITION AND DESCRIPTION OF DIABETES MELLITUS Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of differentorgans, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia. Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome. Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes. The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In the other, much more prevalent category, type 2 diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load. The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process (Fig. 1). A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate glycemic control can be achieved with weight reduction, exercise, and/or oral glucose-lowering agents. These individuals therefore do not require insulin. Other individuals who have some residual insulin secretion but require exogenous insulin for adequate glycemic control can survive without it. Individuals with extensive β-cell destruction and therefore no residual insulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself. Figure 1 Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival. CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATION Assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single class. For example, a person with gestational diabetes mellitus (GDM) may continue to be hyperglycemic after delivery and may be determined to have, in fact, type 2 diabetes. Alternatively, a person who acquires diabetes because of large doses of exogenous steroids may become normoglycemic once the glucocorticoids are discontinued, but then may develop diabetes many years later after recurrent episodes of pancreatitis. Another example would be a person treated with thiazides who develops diabetes years later. Because thiazides in themselves seldom cause severe hyperglycemia, such individuals probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) Immune-mediated diabetes. This form of diabetes, which accounts for only 5–10% of those with diabetes, previously encompassed by the terms insulin-dependent diabetes, type 1 diabetes, or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to GAD (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. In this form of diabetes, the rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual β-cell function sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life. Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. Idiopathic diabetes. Some forms of type 1 diabetes have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance) This form of diabetes, which accounts for ∼90–95% of those with diabetes, previously referred to as non–insulin-dependent diabetes, type 2 diabetes, or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many different causes of this form of diabetes. Although the specific etiologies are not known, autoimmune destruction of β-cells does not occur, and patients do not have any of the other causes of diabetes listed above or below. Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another illness such as infection. This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications. Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal. The risk of developing this form of diabetes increases with age, obesity, and lack of physical activity. It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidemia, and its frequency varies in different racial/ethnic subgroups. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. However, the genetics of this form of diabetes are complex and not clearly defined. Other specific types of diabetes Genetic defects of the β-cell. Several forms of diabetes are associated with monogenetic defects in β-cell function. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action. They are inherited in an autosomal dominant pattern. Abnormalities at six genetic loci on different chromosomes have been identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α. A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. Glucokinase converts glucose to glucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the β-cell. Thus, glucokinase serves as the “glucose sensor” for the β-cell. Because of defects in the glucokinase gene, increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion. The less common forms result from mutations in other transcription factors, including HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1. Point mutations in mitochondrial DNA have been found to be associated with diabetes and deafness The most common mutation occurs at position 3,243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome); however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion. Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern. The resultant glucose intolerance is mild. Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families and is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism. Genetic defects in insulin action. There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes. Therefore, it is assumed that the lesion(s) must reside in the postreceptor signal transduction pathways. Diseases of the exocrine pancreas. Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma. With the exception of that caused by cancer, damage to the pancreas must be extensive for diabetes to occur; adrenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes. This implies a mechanism other than simple reduction in β-cell mass. If extensive enough, cystic fibrosis and hemochromatosis will also damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to the back and pancreatic calcifications identified on X-ray examination. Pancreatic fibrosis and calcium stones in the exocrine ducts have been found at autopsy. Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, respectively) can cause diabetes. This generally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved. Somatostatinoma- and aldosteronoma-induced hypokalemia can cause diabetes, at least in part, by inhibiting insulin secretion. Hyperglycemia generally resolves after successful removal of the tumor. Drug- or chemical-induced diabetes. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate diabetes in individuals with insulin resistance. In such cases, the classification is unclear because the sequence or relative importance of β-cell dysfunction and insulin resistance is unknown. Certain toxins such as Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells. Such drug reactions fortunately are rare. There are also many drugs and hormones that can impair insulin action. Examples include nicotinic acid and glucocorticoids. Patients receiving α-interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency. The list shown in Table 1 is not all-inclusive, but reflects the more commonly recognized drug-, hormone-, or toxin-induced forms of diabetes. Table 1 Etiologic classification of diabetes mellitus Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) Immune mediated Idiopathic Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) Other specific types Genetic defects of β-cell function Chromosome 12, HNF-1α (MODY3) Chromosome 7, glucokinase (MODY2) Chromosome 20, HNF-4α (MODY1) Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4) Chromosome 17, HNF-1β (MODY5) Chromosome 2, NeuroD1 (MODY6) Mitochondrial DNA Others Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes Others Diseases of the exocrine pancreas Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Others Endocrinopathies Acromegaly Cushing's syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others Drug or chemical induced Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide β-adrenergic agonists Thiazides Dilantin γ-Interferon Others Infections Congenital rubella Cytomegalovirus Others Uncommon forms of immune-mediated diabetes “Stiff-man” syndrome Anti-insulin receptor antibodies Others Other genetic syndromes sometimes associated with diabetes Down syndrome Klinefelter syndrome Turner syndrome Wolfram syndrome Friedreich ataxia Huntington chorea Laurence-Moon-Biedl syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome Others Gestational diabetes mellitus Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient. Infections. Certain viruses have been associated with β-cell destruction. Diabetes occurs in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease. Uncommon forms of immune-mediated diabetes. In this category, there are two known conditions, and others are likely to occur. The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. Patients usually have high titers of the GAD autoantibodies, and approximately one-third will develop diabetes. Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby blocking the binding of insulin to its receptor in target tissues. However, in some cases, these antibodies can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycemia. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. As in other states of extreme insulin resistance, patients with anti-insulin receptor antibodies often have acanthosis nigricans. In the past, this syndrome was termed type B insulin resistance. Other genetic syndromes sometimes associated with diabetes. Many genetic syndromes are accompanied by an increased incidence of diabetes. These include the chromosomal abnormalities of Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram's syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of β-cells at autopsy. Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1. Gestational diabetes mellitus For many years, GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Although most cases resolve with delivery, the definition applied whether or not the condition persisted after pregnancy and did not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but its limitations were recognized for many years. As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2 diabetes has increased. After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including the American Diabetes Association (ADA), recommended that high-risk women found to have diabetes at their initial prenatal visit, using standard criteria (Table 3), receive a diagnosis of overt, not gestational, diabetes. Approximately 7% of all pregnancies (ranging from 1 to 14%, depending on the population studied and the diagnostic tests employed) are complicated by GDM, resulting in more than 200,000 cases annually. CATEGORIES OF INCREASED RISK FOR DIABETES In 1997 and 2003, The Expert Committee on Diagnosis and Classification of Diabetes Mellitus (1,2) recognized an intermediate group of individuals whose glucose levels do not meet criteria for diabetes, yet are higher than those considered normal. These people were defined as having impaired fasting glucose (IFG) [fasting plasma glucose (FPG) levels 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)], or impaired glucose tolerance (IGT) [2-h values in the oral glucose tolerance test (OGTT) of 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)]. Individuals with IFG and/or IGT have been referred to as having pre-diabetes, indicating the relatively high risk for the future development of diabetes. IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease. They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Structured lifestyle intervention, aimed at increasing physical activity and producing 5–10% loss of body weight, and certain pharmacological agents have been demonstrated to prevent or delay the development of diabetes in people with IGT; the potential impact of such interventions to reduce mortality or the incidence of cardiovascular disease has not been demonstrated to date. It should be noted that the 2003 ADA Expert Committee report reduced the lower FPG cut point to define IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), in part to ensure that prevalence of IFG was similar to that of IGT. However, the World Health Organization (WHO) and many other diabetes organizations did not adopt this change in the definition of IFG. As A1C is used more commonly to diagnose diabetes in individuals with risk factors, it will also identify those at higher risk for developing diabetes in the future. When recommending the use of the A1C to diagnose diabetes in its 2009 report, the International Expert Committee (3) stressed the continuum of risk for diabetes with all glycemic measures and did not formally identify an equivalent intermediate category for A1C. The group did note that those with A1C levels above the laboratory “normal” range but below the diagnostic cut point for diabetes (6.0 to 100 mg/dl) (5.6 mmol/l) or IGT (2-h glucose > 140 mg/dl) (R.T. Ackerman, personal communication). Other analyses suggest that an A1C of 5.7% is associated with diabetes risk similar to the high-risk participants in the DPP (R.T. Ackerman, personal communication). Hence, it is reasonable to consider an A1C range of 5.7 to 6.4% as identifying individuals with high risk for future diabetes and to whom the term pre-diabetes may be applied if desired. Individuals with an A1C of 5.7–6.4% should be informed of their increased risk for diabetes as well as cardiovascular disease and counseled about effective strategies, such as weight loss and physical activity, to lower their risks. As with glucose measurements, the continuum of risk is curvilinear, so that as A1C rises, the risk of diabetes rises disproportionately. Accordingly, interventions should be most intensive and follow-up should be particularly vigilant for those with A1C levels above 6.0%, who should be considered to be at very high risk. However, just as an individual with a fasting glucose of 98 mg/dl (5.4 mmol/l) may not be at negligible risk for diabetes, individuals with A1C levels below 5.7% may still be at risk, depending on level of A1C and presence of other risk factors, such as obesity and family history. Table 2 summarizes the categories of increased risk for diabetes. Evaluation of patients at risk should incorporate a global risk factor assessment for both diabetes and cardiovascular disease. Screening for and counseling about risk of diabetes should always be in the pragmatic context of the patient's comorbidities, life expectancy, personal capacity to engage in lifestyle change, and overall health goals. Table 2 Categories of increased risk for diabetes* FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) [IFG] 2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT] A1C 5.7–6.4% *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range. DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS For decades, the diagnosis of diabetes has been based on glucose criteria, either the FPG or the 75-g OGTT. In 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus revised the diagnostic criteria, using the observed association between FPG levels and presence of retinopathy as the key factor with which to identify threshold glucose level. The Committee examined data from three cross-sectional epidemiologic studies that assessed retinopathy with fundus photography or direct ophthalmoscopy and measured glycemia as FPG, 2-h PG, and A1C. These studies demonstrated glycemic levels below which there was little prevalent retinopathy and above which the prevalence of retinopathy increased in an apparently linear fashion. The deciles of the three measures at which retinopathy began to increase were the same for each measure within each population. Moreover, the glycemic values above which retinopathy increased were similar among the populations. These analyses helped to inform a new diagnostic cut point of ≥126 mg/dl (7.0 mmol/l) for FPG and confirmed the long-standing diagnostic 2-h PG value of ≥200 mg/dl (11.1 mmol/l). A1C is a widely used marker of chronic glycemia, reflecting average blood glucose levels over a 2- to 3-month period of time. The test plays a critical role in the management of the patient with diabetes, since it correlates well with both microvascular and, to a lesser extent, macrovascular complications and is widely used as the standard biomarker for the adequacy of glycemic management. Prior Expert Committees have not recommended use of the A1C for diagnosis of diabetes, in part due to lack of standardization of the assay. However, A1C assays are now highly standardized so that their results can be uniformly applied both temporally and across populations. In their recent report (3), an International Expert Committee, after an extensive review of both established and emerging epidemiological evidence, recommended the use of the A1C test to diagnose diabetes, with a threshold of ≥6.5%, and ADA affirms this decision. The diagnostic A1C cut point of 6.5% is associated with an inflection point for retinopathy prevalence, as are the diagnostic thresholds for FPG and 2-h PG (3). The diagnostic test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial reference assay. Point-of-care A1C assays are not sufficiently accurate at this time to use for diagnostic purposes. There is an inherent logic to using a more chronic versus an acute marker of dysglycemia, particularly since the A1C is already widely familiar to clinicians as a marker of glycemic control. Moreover, the A1C has several advantages to the FPG, including greater convenience, since fasting is not required, evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness. These advantages, however, must be balanced by greater cost, the limited availability of A1C testing in certain regions of the developing world, and the incomplete correlation between A1C and average glucose in certain individuals. In addition, the A1C can be misleading in patients with certain forms of anemia and hemoglobinopathies, which may also have unique ethnic or geographic distributions. For patients with a hemoglobinopathy but normal red cell turnover, such as sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used (an updated list is available at www.ngsp.org/prog/index3.html). For conditions with abnormal red cell turnover, such as anemias from hemolysis and iron deficiency, the diagnosis of diabetes must employ glucose criteria exclusively. The established glucose criteria for the diagnosis of diabetes remain valid. These include the FPG and 2-h PG. Additionally, patients with severe hyperglycemia such as those who present with severe classic hyperglycemic symptoms or hyperglycemic crisis can continue to be diagnosed when a random (or casual) plasma glucose of ≥200 mg/dl (11.1 mmol/l) is found. It is likely that in such cases the health care professional would also measure an A1C test as part of the initial assessment of the severity of the diabetes and that it would (in most cases) be above the diagnostic cut point for diabetes. However, in rapidly evolving diabetes, such as the development of type 1 diabetes in some children, A1C may not be significantly elevated despite frank diabetes. Just as there is less than 100% concordance between the FPG and 2-h PG tests, there is not full concordance between A1C and either glucose-based test. Analyses of NHANES data indicate that, assuming universal screening of the undiagnosed, the A1C cut point of ≥6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of ≥126 mg/dl (7.0 mmol/l) (cdc website tbd). However, in practice, a large portion of the population with type 2 diabetes remains unaware of their condition. Thus, it is conceivable that the lower sensitivity of A1C at the designated cut point will be offset by the test's greater practicality, and that wider application of a more convenient test (A1C) may actually increase the number of diagnoses made. Further research is needed to better characterize those patients whose glycemic status might be categorized differently by two different tests (e.g., FPG and A1C), obtained in close temporal approximation. Such discordance may arise from measurement variability, change over time, or because A1C, FPG, and postchallenge glucose each measure different physiological processes. In the setting of an elevated A1C but “nondiabetic” FPG, the likelihood of greater postprandial glucose levels or increased glycation rates for a given degree of hyperglycemia may be present. In the opposite scenario (high FPG yet A1C below the diabetes cut point), augmented hepatic glucose production or reduced glycation rates may be present. As with most diagnostic tests, a test result diagnostic of diabetes should be repeated to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such as a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, there are scenarios in which results of two different tests (e.g., FPG and A1C) are available for the same patient. In this situation, if the two different tests are both above the diagnostic thresholds, the diagnosis of diabetes is confirmed. On the other hand, when two different tests are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the FPG ( 126 mg/dl (7.0 mmol/l) or a casual plasma glucose >200 mg/dl (11.1 mmol/l) meets the threshold for the diagnosis of diabetes. In the absence of unequivocal hyperglycemia, the diagnosis must be confirmed on a subsequent day. Confirmation of the diagnosis precludes the need for any glucose challenge. In the absence of this degree of hyperglycemia, evaluation for GDM in women with average or high-risk characteristics should follow one of two approaches. One-step approach. Perform a diagnostic OGTT without prior plasma or serum glucose screening. The one-step approach may be cost-effective in high-risk patients or populations (e.g., some Native-American groups). Two-step approach. Perform an initial screening by measuring the plasma or serum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT. When the two-step approach is used, a glucose threshold value >140 mg/dl (7.8 mmol/l) identifies ∼80% of women with GDM, and the yield is further increased to 90% by using a cutoff of >130 mg/dl (7.2 mmol/l). With either approach, the diagnosis of GDM is based on an OGTT. Diagnostic criteria for the 100-g OGTT are derived from the original work of O'Sullivan and Mahan (12) modified by Carpenter and Coustan (11) and are shown at the top of Table 4. Alternatively, the diagnosis can be made using a 75-g glucose load and the glucose threshold values listed for fasting, 1 h, and 2 h (Table 4, bottom); however, this test is not as well validated as the 100-g OGTT. Table 4 Diagnosis of GDM with a 100-g or 75-g glucose load mg/dl mmol/l 100-g glucose load Fasting 95 5.3 1-h 180 10.0 2-h 155 8.6 3-h 140 7.8 75-g glucose load Fasting 95 5.3 1-h 180 10.0 2-h 155 8.6 Two or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis. The test should be done in the morning after an overnight fast of between 8 and 14 h and after at least 3 days of unrestricted diet (≥150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated and should not smoke throughout the test. Results of the Hyperglycemia and Adverse Pregnancy Outcomes study (13), a large-scale (∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. The IADPSG recommended that all women not known to have prior diabetes undergo a 75-g OGTT at 24–28 weeks of gestation. The group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with women with the mean glucose levels in the HAPO study. At the time of publication of this update, ADA is planning to work with U.S. obstetrical organizations to consider adoption of the IADPSG diagnostic criteria and to discuss the implications of this change. While this change will significantly increase the prevalence of GDM, there is mounting evidence that treating even mild GDM reduces morbidity for both mother and baby (14).
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The mechanisms of action of metformin
Graham Rena, D Hardie, Ewan Pearson (2017)
Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4342-z) contains a slideset of the figures for download, which is available to authorised users.
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Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes
Ralph A. DeFronzo, Devjit Tripathy (2009)
Insulin resistance is a characteristic feature of type 2 diabetes and plays a major role in the pathogenesis of the disease (1,2). Although β-cell failure is the sine qua non for development of type 2 diabetes, skeletal muscle insulin resistance is considered to be the initiating or primary defect that is evident decades before β-cell failure and overt hyperglycemia develops (3,4). Insulin resistance is defined as a reduced response of target tissues (compared with subjects with normal glucose tolerance [NGT] without a family history of diabetes), such as the skeletal muscle, liver, and adipocytes, to insulin. Because skeletal muscle is the predominant site of insulin-mediated glucose uptake in the postprandial state, here we will focus on recent advances about the time of onset, as well as the mechanism, of the skeletal muscle insulin resistance. RESEARCH DESIGN AND METHODS The euglycemic insulin clamp technique (5) is considered to be the gold standard for measuring insulin action in vivo. With this technique, whole-body insulin action is quantified as the rate of exogenous glucose infusion (plus any residual hepatic glucose production) required to maintain the plasma glucose concentration at euglycemic levels in response to a fixed increment in the plasma insulin concentration. Because 80–90% of the infused glucose is taken up by skeletal muscle under conditions of euglycemic hyperinsulinemia, insulin sensitivity measured with the insulin clamp technique primarily reflects skeletal muscle (6). Another advantage of this technique is that it can be combined with indirect calorimetry to measure different substrate oxidation rates and with muscle biopsy to examine the biochemical/molecular etiology of the insulin resistance. Measurement of insulin sensitivity by the frequently sampled intravenous glucose tolerance test reflects both hepatic and peripheral insulin resistance and correlates well with the insulin clamp technique (7). Because insulin clamp studies are not feasible in large epidemiological studies, other surrogate markers of insulin sensitivity from glucose and insulin values in the fasting state or after an oral glucose tolerance test (OGTT) have been developed (8 –10). The homeostatic model assessment correlates reasonably well with the insulin clamp (10), but it primarily reflects hepatic insulin sensitivity, since the fasting plasma glucose is determined mainly by the rate of hepatic glucose production (HGP) and insulin is the primary regulator of HGP. The correlation between homeostatic model assessment and the insulin clamp also is less robust when analyzed in subgroups of glucose tolerance (11). During an OGTT, significant (∼30–40%) amounts of glucose are taken up by the splanchnic bed, and HGP is less completely suppressed than during the insulin clamp technique (12). As a result, the plasma glucose concentration during OGTT is affected by both hepatic and peripheral (primarily muscle) insulin resistance. Therefore, indexes of insulin resistance from the OGTT, e.g., the Matsuda index, reflect both hepatic and peripheral insulin resistance and correlate well (R value ∼0.70) with insulin sensitivity measured with the euglycemic insulin clamp (9). Normal glucose homeostasis Skeletal muscle is the major site of glucose uptake in the postprandial state in humans. Under euglycemic hyperinsulinemic conditions, ∼80% of glucose uptake occurs in skeletal muscle (13). Studies using the euglycemic hyperinsulinemic clamp and femoral artery/vein catheterization to quantitate glucose uptake have allowed investigators to quantify leg muscle glucose uptake. Because adipose tissue uses 80–90%) of glucose disposal during the euglycemic insulin clamp occurs in muscle, these results demonstrate that a physiologic elevation in the plasma insulin concentration will exacerbate the underlying muscle insulin resistance. Iozzo et al. (53) performed a 240-min euglycemic insulin clamp study with muscle biopsies in healthy volunteers. Subjects then received a low-dose insulin infusion for 72 h (plasma insulin concentration 143 ± 25 pmol/l [21 ± 2 μU/ml]), followed by a repeat insulin clamp with muscle biopsies. After 72 h of sustained physiologic hyperinsulinemia, insulin-stimulated muscle glycogen synthase activity, total body glucose uptake, and nonoxidative glucose disposal (primarily reflects glycogen synthesis in muscle) were significantly reduced. Taken together, these findings indicate that hyperinsulinemia is not only a compensatory response to insulin resistance, but also a self-perpetuating cause of the defect in muscle insulin action. Molecular etiology of the skeletal muscle insulin resistance in genetically predisposed individuals Using the euglycemic insulin clamp with skeletal muscle biopsy, a number of investigators have examined the insulin signal transduction system in human skeletal muscle of type 2 diabetic subjects and consistently demonstrated defects in IRS-1 tyrosine phosphorylation and PI-3 kinase and Akt activation (26,54,55). To examine whether similar defects are present in genetically predisposed individuals, Pratipanawatr et al. (36) examined insulin signaling in NGT subjects with a strong family history of type 2 diabetes and demonstrated that both the basal and insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity associated with IRS-1 were significantly decreased (Fig. A10). Insulin stimulation of PI 3-kinase activity is a requisite for activation of glucose transport and glycogen synthesis. Increased serine phosphorylation of IRS-1 has been shown to impair insulin signaling (tyrosine phosphorylation of both insulin resistance and IRS-1) in type 2 diabetes (56). In lean insulin-resistant NGT offspring of type 2 diabetic parents, increased serine phosphorylation of IRS-1 in skeletal muscle has been documented in association with impaired activation of Akt (57) (Fig. A11). Thus, at the earliest stage in the natural history of type 2 diabetes, i.e., the NGT insulin-resistant offspring of two type 2 diabetic parents, the molecular etiology of the muscle insulin resistance already is well established and is virtually identical to that in their diabetic parents. Relationship between muscle insulin resistance and altered FFA/muscle lipid metabolism Gulli et al. (32) were the first to demonstrate that the NGT offspring of two type 2 diabetic parents demonstrated marked muscle insulin resistance but normal sensitivity to the suppressive effect of insulin on hepatic glucose production. However, a normal basal rate of HGP in the face of fasting hyperinsulinemia could be construed to indicate the presence of hepatic insulin resistance. More impressive was the elevated fasting plasma FFA concentration in the presence of fasting hyperinsulinemia and the impaired suppression of plasma FFA during the euglycemic insulin clamp (Fig. A12). These findings indicate the presence of marked adipocyte resistance to the antilipolytic effect of insulin. Impaired insulin-mediated suppression of whole-body lipid oxidation also was present in the NGT offspring (Fig. A12). Petersen et al. (58) documented an increase in intramyocellular lipid content in the offspring of two type 2 diabetic parents. This observation is of important clinical significance, since diacylglycerol, long-chain fatty acyl CoAs, and ceramides all have been shown to cause serine phosphorylation of insulin resistance and IRS-1 and lead to the development of insulin resistance in skeletal muscle (59,60). Collectively, these results suggest that intramyocellular accumulation of toxic lipid metabolites plays an important role in the pathogenesis of muscle insulin resistance. To further address this question, Kashyap et al. (30) infused a lipid emulsion for 4 days to cause a physiologic elevation in the plasma FFA concentration in NGT insulin-resistant offspring of two type 2 diabetes parents and in NGT insulin-sensitive subjects without any family history of diabetes. Four days of physiological elevation in the plasma FFA concentration in the offspring did not cause any further worsening of insulin-stimulated whole-body glucose disposal, nonoxidative glucose disposal, glucose oxidation, or preexisting defects in insulin-stimulated insulin receptor tyrosine phosphorylation (30). In contrast, in healthy control subjects, chronic lipid infusion was associated with a marked decline in insulin-stimulated glucose uptake and insulin receptor tyrosine phosphorylation (30). When the insulin-resistant offspring were treated with acipimox for 7 days to reduce the plasma FFA concentration and intramyocellular FACoA concentration, a marked improvement in insulin sensitivity was observed (61). These data lend further support to the observation that insulin resistance in skeletal muscle is an early metabolic defect in the pathogenesis of type 2 diabetes and that muscle lipid accumulation plays a central role in the etiology of the muscle insulin resistance. Mitochondria are the main organelles where fatty acids are oxidized and investigators have focused on their structure and function in patients with type 2 diabetes. Studies using the leg balance technique have documented that fat oxidation is reduced in both type 2 diabetic and obese insulin-resistant nondiabetic individuals (62), suggesting that muscle mitochondrial oxidative capacity is impaired. Recently, two groups independently showed that NGT offspring of two type 2 diabetic parents had a reduced expression of key mitochondrial genes involved in the regulation of oxidative metabolism in skeletal muscle (63,64). The most commonly underexpressed functional genes were those coding for energy generation, including multiple glycolytic, tricarboxylic acid cycle, and oxidative phosphorylation genes. Evidence in support of a role for mitochondrial dysfunction as a cause of muscle insulin resistance in the NGT offspring of two type 2 diabetic parents has been provided by Shulman and colleagues. Using 31P-NMR, these investigators demonstrated impaired mitochondrial activity in NGT insulin-resistant offspring of type 2 diabetic parents (57,58,65). Whereas mitochondria from NGT subjects without any family history of diabetes responded to insulin by increasing ATP production by 90%, mitochondria from insulin-resistant offspring increased ATP production by only 5% (Fig. A13). The authors postulated that muscle mitochondrial dysfunction was the primary defect, leading to elevated intramyocellular fatty acid metabolites (as a consequence of reduced fat oxidation) and subsequent insulin resistance (58,66). However, recent studies by Abdul-Ghani et al. (67) have shown that even small increases in palmitoyl carnitine (5–10 μmol/l) can markedly impair ATP synthesis in mitochondria isolated from human muscle. Thus, it is unclear which is the cart and which is the horse: mitochondrial dysfunction leading to increased intramyocellular lipid content and insulin resistance or increased muscle lipid content (i.e., secondary to elevated plasma FFA levels and/or excessive lipid ingestion) leading to mitochondrial dysfunction and insulin resistance. SUMMARY The maintenance of normal glucose homeostasis depends on a finely balanced dynamic interaction between tissue (muscle, liver, and fat) sensitivity to insulin and insulin secretion. Even in the presence of severe insulin resistance, a perfectly normal β-cell is capable of secreting sufficient amounts of insulin to offset the defect in insulin action. Thus, the evolution of type 2 diabetes requires the presence of defects in both insulin secretion and insulin action, and both of these defects can have a genetic as well as an acquired component. When type 2 diabetic patients initially present to the physician, they will have had their diabetes for many years, and defects in insulin action (in muscle, liver, and adipocytes) and insulin secretion will be well established (1,2,39). At this stage, it is not possible to define which defect came first in the natural history of the disease and which tissue is the primary defect responsible for the insulin resistance. Although insulin resistance represents the earliest detectable abnormality in the great majority of type 2 diabetic people, in a minority of individuals (i.e., glucokinase deficiency), it is clear that a β-cell defect initiates the disturbance in glucose homeostasis. Nevertheless, it is now clear that in any given diabetic patient, whatever defect (insulin resistance or impaired insulin secretion) initiates the disturbance in glucose metabolism, it will eventually be followed by the emergence of its counterpart (Fig. A14). Insulin resistance is a nearly universal finding in patients with established type 2 diabetes. In normal-weight and obese individuals with IGT and in type 2 diabetic subjects with mild fasting hyperglycemia (110–140 mg/dl, 6.1–7.8 mmol/l), both the basal and glucose-stimulated plasma insulin levels are increased. Although the first-phase insulin response may be decreased in some, but not all, of these subjects, the first phase consistently is increased in the NGT offspring of two type 2 diabetic parents and the total insulin response is increased in NGT offspring and in IGT subjects. In each of these groups, tissue sensitivity to insulin, measured with the insulin clamp technique, has been shown to be diminished. Prospective studies conclusively have demonstrated that hyperinsulinemia and insulin resistance precede the development of IGT and that IGT represents the forerunner of type 2 diabetes. This scenario has been well documented in Pima Indians, Mexican Americans, and Pacific Islanders. It is noteworthy that all of these populations are characterized by obesity and a younger age at onset of diabetes. Such results provide conclusive evidence that insulin resistance is the inherited defect that initiates the diabetic condition in the majority of type 2 diabetic patients. Studies in NGT first-degree relatives of diabetic individuals and in the offspring of two diabetic parents indicate that the inherited defect in insulin action results from an abnormality in the glycogen synthetic pathway in muscle and more proximal defects in glucose transport/phosphorylation and insulin signal transduction. As the insulin resistance progresses and muscle glucose uptake becomes further impaired, the postprandial rise in plasma glucose concentration becomes excessive, but the increase in basal hyperinsulinemia is sufficient to maintain the fasting plasma glucose concentration and HGP within the normal range. Nonetheless, there is an excessive postprandial rise in plasma glucose concentration, and a longer time is required to restore normoglycemia after each meal. Eventually, however, the insulin resistance becomes so severe that the compensatory hyperinsulinemia is no longer sufficient to maintain the fasting glucose concentration at the basal level. The development of hyperglycemia further stimulates β-cell secretion of insulin, and the resultant hyperinsulinemia causes a downregulation of insulin receptor number and of the intracellular events involved in insulin action, thus exacerbating the insulin resistance. Initially, the hyperglycemia-induced increase in insulin secretion serves a compensatory function to maintain near-NGT. In some individuals, the persistent stimulus to the β-cell to oversecrete insulin leads to a progressive loss of β-cell function. Chronic hyperglycemia (glucose toxicity) and/or disturbances in lipid metabolism (lipotoxicity) may contribute to the defect in insulin secretion. The resultant insulinopenia leads to the emergence/exacerbation of postreceptor defects in insulin action. Many of the intracellular events involved in glucose metabolism depend on the surge of insulin that occurs three to four times per day in response to nutrient ingestion. When the insulin response becomes deficient, the activity of the glucose transport system becomes severely impaired and a number of key intracellular enzymatic steps involved in glucose metabolism become depressed. Additionally, when severe insulinopenia ensues, plasma FFA levels rise, further contributing to the defects in intracellular glucose disposal. There is also compelling evidence that hyperglycemia per se can downregulate the glucose transport system, as well as a number of other intracellular events involved in insulin action (glucose toxicity), and a similar argument can be made concerning the intracellular derangement in lipid metabolism. This pathogenetic sequence can explain all of the clinical and laboratory features observed in type 2 diabetic patients. Insofar as the cellular defect is generalized, both hepatic and peripheral tissues (skeletal muscle and adipocytes), and possibly the β-cells themselves, would manifest insulin resistance, and the numerous metabolic alterations characteristic of the diabetic state could be related to one and the same primary defect. The NGT offspring of two type 2 diabetic parents also manifest marked adipocyte resistance to the suppressive effects of insulin on lipolysis. One could argue, therefore, that the adipocyte represents the primary tissue responsible for the insulin resistance. According to this scenario, the elevated plasma FFA levels produce insulin resistance in muscle and liver and impair β-cell function. Adipocytes in the NGT offspring of two type 2 diabetic parents also secrete excessive amounts of inflammatory and insulin resistance producing adipocytokines that could initiate/exacerbate the insulin resistance in skeletal muscle. As reviewed by Iozzo in this symposium, the adipocyte insulin resistance could be genetic in origin or induced in utero during the third trimester by nutritional deprivation or overfeeding. There is less evidence to support a role for the liver as the organ responsible for the insulin resistance. However, the NGT offspring of two type 2 diabetic parents have a normal rate of HGP in the presence of fasting hyperinsulinemia, suggesting the presence of hepatic resistance to the suppressive effect of insulin on glucose production. Therefore, one could argue that the resultant fasting hyperinsulinemia leads to the development of insulin resistance in skeletal muscle.
Author and article information
Journal
Journal ID (nlm-ta): Rev Diabet Stud
Journal ID (iso-abbrev): Rev Diabet Stud
Journal ID (publisher-id): RDS
Title:
The Review of Diabetic Studies : RDS
Publisher:
SBDR - Society for Biomedical Diabetes Research
ISSN
(Print):
1613-6071
ISSN
(Electronic):
1614-0575
Publication date
(Electronic):
01
May
2021
Publication date Collection: 2020
Volume: 16
Issue: 1
Pages: 13-23
Affiliations
[1
]Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Ahmedabad,
India.
Author notes
Address correspondence to: Abhijeet S. Kate, e-mail:
kate.abhi.s@
123456gmail.com
or Alok Jain, e-mail:
alokjain16@
123456gmail.com
Article
Publisher ID: RDS-16-013DOI: 10.1900/RDS.2020.16.13
PMC ID: 9380092
PubMed ID: 33905469
SO-VID: 1bad9c54-d71a-451d-a3a1-4338360ab281
Copyright © Copyright © by Lab & Life Press
License:
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 Unported (CC BY 4.0) ( https://creativecommons.org/licenses/by/4.0/)
History
Date
received
: 23
July
2020
Date
revision received
: 12
September
2020
Date
accepted
: 17
October
2020
Categories
Subject:
Review
Data availability: