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Cited by 451Diabetes, Cardiovascular Risks, and LipoproteinsPancreatic function and diabetesDiabetes Management and Research

The DOI matches its Crossref record; 142 of the 150 references it cites were found in a registry or an index.

Insulin Resistance versus Insulin Deficiency in Non-Insulin-Dependent Diabetes Mellitus: Problems and Prospects

Ferrannini, Ele·1998·Endocrine Reviews
DOI 10.1210/edrv.19.4.0336
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Abstract

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin

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Research works printed but not linked: 22

  1. 1985, Technical Report Series 727
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  3. Yki-Järvinen, 1992, Glucose toxicity., Endocr Rev, 13, 415
  4. Del Prato, 1986, Evaluation of insulin sensitivity in man In: Clarke WL, Larner J, Pohl SL (eds) Methods in Diabetes Research. Clinical Methods., John Wiley & Sons, New York, vol, 2, 35
  5. Kahn, 1997, Insulin secretion in the normal and diabetic human, In: Alberti KGMM, Zimmet P, DeFronzo RA, Keen H (Honorary) (eds) International Textbook of Diabetes Mellitus, ed. 2. John Wiley & Sons Ltd, Chichester, U.K., vol, 1, 337
  6. Rewers, 1995, Risk factors for non-insulin-depedent diabetes, In: Diabetes in America, ed. 2. NIH Publication No. 95–1468. National Institutes of Health, Bethesda, MD, pp, 179
  7. Vaag, 1992, Decreased insulin activation of glycogen synthase in skeletal muscles of young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus., J Clin Invest, 89, 782, 10.1172/JCI115656 · DOI · Paper page
  8. Vaag, 1997, Metabolic impact of family history of NIDDM, Diabetologia, 40, A4
  9. Buchanan, 1995, The pathogenesis of GDM: implications for diabetes after pregnancy., Diabetes Rev, 3, 584
  10. Porte Jr, 1990, Neural regulation of islet hormones and its role in energy balance and stress hyperglycemia, In: Rifkin H, Porte Jr D (eds) Diabetes Mellitus: Theory and Practice. Elsevier, New York, pp, 175
  11. Leahy, 1996, Detrimental effects of chronic hyperglycemia on the pancreatic β-cell, In: LeRoith D, Taylor SI, Olefsky JM (eds) Diabetes Mellitus. A Fundamental and Clinical Text. Lippincott-Raven Publishers, Philadelphia, pp, 103
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  13. Eriksson, 1997, Skeletal muscle triglycerides in impaired glucose tolerance and NIDDM, Diabetologia, 40, A286
  14. Hanis, 1997, Power considerations in the genetics of diabetes and other common chronic conditions., Diabetes Rev, 5, 270
  15. Bell, 1997, Genetics of NIDDM in the Mexican-Americans of Starr County, Texas: an update., Diabetes Rev, 5, 277
  16. Philippe, 1994, Pancreatic expression of the insulin and glucagon genes: update 1994. In: Underwood LE, Negro-Vilar A (eds) The Endocrine Pancreas, Insulin Action, and Diabetes., Endocrine Reviews Monographs, The Endocrine Society, Bethesda, MD, vol, 2, 21
  17. Taylor, 1994, Mutations in the insulin receptor gene: update 1994. In: Underwood LE, Negro-Vilar A (eds) The Endocrine Pancreas, Insulin Action, and Diabetes., Endocrine Reviews Monographs, The Endocrine Society, Bethesda, MD, vol, 2, 58
  18. Steiner, 1995, Familial syndromes of hyperproinsulinemia and hyperinsulinemia with muld diabetes, In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, pp, 897
  19. Ferrannini, 1995, Primary insulin resistance: a risk syndrome, In: Leslie RDG, Robbins DC (eds), Diabetes: Clinical Science in Practice. Cambridge University Press, Cambridge, U.K., pp, 200
  20. Paolisso, 1993, Metabolic features of patients with and without coronary heart disease but with a superimposable cluster of cardiovascular risk factors., Coron Artery Dis, 4, 1085, 10.1097/00019501-199312000-00008 · DOI
  21. Stokes, 1985, The independent contribution of various indices of obesity on the 22-yr incidence of coronary artery disease: the Framingham Heart Study, In: Vague J, Björntorp P, Guy-Grand B, Rebuffé-Scrive M, Vague P (eds) Proceedings of the International Symposium on the Metabolic Complications of Human Obesities, Marseille, France. ICS No. 682. Elsevier, Amsterdam, pp, 49
  22. Bilous, 1997, Clinical aspects of nephropathy, In: Alberti KGMM, Zimmet P, DeFronzo RA, Keen H (Honorary) (eds) International Textbook of Diabetes Mellitus. ed. 2. John Wiley & Sons Ltd, Chichester, U.K., vol, 2, 1362

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Metadata

Authors
Ferrannini, E.
Affiliations
University of Pisa (IT)
Corresponding author
Ferrannini, Ele
ORCID
Ferrannini, Ele
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
1998-08-01
Volume
19
Issue
4
Pages
477-490
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/edrv.19.4.0336
OpenAlex
W2166439032
Cited by
451
References
150
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 12 · 2021: 10 · 2020: 14 · 2019: 13 · 2018: 11 · 2017: 7 · 2016: 16 · 2015: 12 · 2014: 8 · 2013: 20 · 2012: 21
FWCI
8.72
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
insulin resistance, insulin deficiency, type 2 diabetes, diabetes etiology, beta-cell dysfunction, impaired insulin secretion, impaired glucose tolerance, skeletal muscle insulin resistance, genetic susceptibility, type 1 diabetes, maturity-onset diabetes of the young, mitochondrial mutations, prediabetes, glucose transport, glycogen
MeSH terms
Diabetes Mellitus, Type 2, Humans, Insulin, Insulin Resistance

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