Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Section 3: Phasic Insulin Release and Metabolic Control

Is Reduced First-Phase Insulin Release the Earliest Detectable Abnormality in Individuals Destined to Develop Type 2 Diabetes?

  1. John E. Gerich
  1. From the Department of Medicine, University of Rochester, Rochester, New York
    Diabetes 2002 Feb; 51(suppl 1): S117-S121. https://doi.org/10.2337/diabetes.51.2007.S117
    PreviousNext
    • Article
    • Figures & Tables
    • Info & Metrics
    • PDF
    Loading

    Abstract

    Insulin is released from the pancreas in a biphasic manner in response to a square-wave increase in arterial glucose concentration. The first phase consists of a brief spike lasting ∼10 min followed by the second phase, which reaches a plateau at 2–3 h. It is widely thought that diminution of first-phase insulin release is the earliest detectable defect of β-cell function in individuals destined to develop type 2 diabetes and that this defect largely represents β-cell exhaustion after years of compensation for antecedent insulin resistance. In this article, the origins of these concepts are reviewed and recent evidence is presented suggesting that reductions in both phases of insulin release are equally early, that they precede insulin resistance other than that simply due to obesity, and that they therefore may represent the primary genetic risk factor predisposing individuals to type 2 diabetes.

    The kinetics of insulin release and its implications for normal physiology and the pathogenesis of type 2 diabetes were the main themes of this symposium. It has been known for nearly 40 years that insulin secretion is biphasic (1) (i.e., in response to a square-wave hyperglycemic stimulus to either the in vitro perfused rat pancreas or the in vivo human pancreas) and that insulin concentrations in perfusate and plasma increase rapidly to a peak at 2–4 min, decrease to a nadir at 10–15 min, and then gradually increase progressively to a pseudo-steady state at 2–3 h. The initial spike response is generally referred to as first-phase insulin release, and the subsequent increase in insulin secretion is considered to represent the second-phase insulin release.

    The earliest detectable defect in β-cell function is commonly thought to be a reduction in first-phase insulin release (2). This concept arose largely based on cross-sectional studies of individuals with various degrees of glucose tolerance that examined only first-phase insulin responses after intravenous injection of insulin. These studies found that first-phase insulin was reduced in individuals with plasma glucose in upper ranges of normal and was essentially absent in people with fasting hyperglycemia (3,4). The concept received further support from studies of people with impaired glucose tolerance (IGT), a precursor of type 2 diabetes, showing that these individuals generally had reduced plasma insulin levels at 30 min after glucose ingestion and “normal or increased” plasma insulin levels at 120 min (5). The assumption has been generally made that the 30-min response reflected first-phase insulin release, whereas the 120-min response reflected second-phase insulin release. Because insulin released early after glucose ingestion has been shown to be a key determinant of subsequent plasma glucose responses (6,7), it became widely accepted that reduced first-phase insulin release is responsible for the development of IGT.

    It should be noted, however, that the so-called “normal or increased” 120-min plasma insulin levels may not have been appropriate for the prevailing glycemic stimulus (8). Thus, if these late insulin responses reflect second-phase insulin release, this phase of insulin secretion may also have been reduced.

    A related issue for individuals interested in the pathogenesis of type 2 diabetes is the debate as to whether insulin resistance or impaired β-cell function is the primary defect. By primary defect, the underlying genetic defect is meant. It seems pretty well established that type 2 diabetes is a polygenic disorder in which both hereditary and environmental or acquired factors are involved (9), and both of these factors can affect β-cell function and insulin sensitivity (10,11). From the elegant studies of Bergman et al. (12) and Kahn et al. (13), we know that the normal islet adjusts its function to compensate for insulin resistance, and, thus, in interpreting the appropriateness of insulin secretion, we must take into consideration not only the stimulus (i.e., plasma glucose level), but also the prevailing insulin sensitivity. For example, during a hyperglycemic clamp experiment in which plasma glucose was increased to comparable levels in a lean and an obese individual, plasma insulin responses in the lean individual compared with those of the obese individual would be inappropriate and signify impaired β-cell function.

    Unfortunately, in the past, these variables were generally not taken into consideration and because of this, the concept that insulin resistance precedes β-cell failure in the progression to type 2 diabetes became widely believed (14) and consequently so did the concept that insulin resistance was the primary genetic component of type 2 diabetes (15). Such a concept fails to explain why most obese individuals, who of course are insulin resistant, do not develop diabetes. If one accepts that the normal β-cell adjusts its function to compensate for insulin resistance, then one could explain the development of IGT and type 2 diabetes as a failure of β-cell compensation and that this may be the genetic basis for type 2 diabetes. Acceptance of this proposition does not exclude that environmental/acquired factors (e.g., glucose toxicity [16], lipotoxicity [17], and amyloid accumulation in islets [18]) might also be involved.

    In this article, previously published work of the author’s laboratory is reviewed as is that of other investigators that relates to the questions of whether first-phase insulin release is the earliest detectable defect in β-cell function and whether impaired β-cell function precedes insulin resistance in the pathogenesis of type 2 diabetes.

    FIRST-PHASE VERSUS SECOND-PHASE INSULIN RELEASE

    During the past 10 years, as part of a multinational collaborative project involving centers in the U.S., Finland, Norway, Greece, and Italy, we have been investigating β-cell function and insulin sensitivity in nondiabetic individuals with and without a first-degree relative with type 2 diabetes (19–21). These individuals were all Caucasian and had either normal or impaired glucose tolerance according to World Health Organization criteria. To evaluate individual phases of insulin release and insulin sensitivity, 3-h hyperglycemic glucose clamps were used. First-phase insulin release was taken as the sum of the increments in plasma insulin over the initial 10 min, and second-phase insulin release was taken as the average plasma insulin level or increment during the last hour of the clamp. Insulin sensitivity was calculated as the glucose infusion rate necessary to maintain the clamp during the last hour divided by the plasma insulin level during that period. The basis for this was the assumption that the glucose infusion rate would depend on the prevailing insulinemia and the responsiveness of tissues to that insulin. Because the glucose infusion rate reflects the sum of the suppression of endogenous glucose release and the stimulation of glucose disposal, it represents whole-body insulin sensitivity. In addition, this approach assumes that the effect of the hyperglycemia per se to suppress endogenous glucose release and to augment glucose disposal is negligible compared with the effects of insulin. Insulin sensitivity assessed with the hyperglycemic clamp has been shown to be highly correlated to that determined with the euglycemic-hyperinsulinemic clamp (22).

    To date, we have studied 185 individuals with normal glucose tolerance and 98 people with IGT. Their clinical characteristics are shown in Table 1. Because significant differences were observed between the groups for age, BMI, and waist-to-hip ratio, which are known to affect β-cell function and insulin sensitivity, these factors as well as sex were used as covariates for statistical comparisons of β-cell function and insulin sensitivity.

    Figure 1 gives the plasma glucose and insulin levels during the hyperglycemic clamp experiments broken down into four groups: those with normal glucose tolerance with (1) and without (2) a first-degree relative with type 2 diabetes and those having IGT with (3) and without (4) a first-degree relative with type 2 diabetes. It is clear that the hyperglycemic stimulus for insulin secretion was comparable in all groups.

    As shown in Table 2, both first- and second-phase insulin release were reduced in people with IGT, as was insulin sensitivity. These data therefore do not provide evidence for priority for reductions in first-phase insulin release versus second-phase insulin release or for insulin resistance preceding impaired β-cell function. However, because first-phase insulin release was reduced by ∼35% and second-phase insulin release was reduced by ∼28%, whereas insulin sensitivity was reduced by ∼15%, it appears that the decrement in β-cell function was greater than that in insulin sensitivity.

    Table 2 also provides data on differences in the phases of insulin release and insulin sensitivity in individuals with and without a family history of diabetes. As has been previously reported (19–28), there was clear-cut evidence for reduced β-cell function in individuals with a family history of diabetes. Both phases of insulin release were reduced: first phase slightly more than second phase (∼19 vs. ∼12%). It is of note that insulin sensitivity was not reduced in these subjects.

    We have not as yet analyzed these data to examine the coincidence of reductions in first- and second-phase insulin release, but in an earlier study of subjects with normal glucose tolerance, differing only in whether they had a first-degree relative with type 2 diabetes (19), we also found that people with a first-degree relative with type 2 diabetes had reduced β-cell function (but no insulin resistance) and that some had reductions in only first-phase insulin release; some had reductions only in second-phase insulin release, whereas others had reductions in both phases of insulin release. We interpret these results to be consistent with genetic heterogeneity for impaired β-cell function.

    IMPAIRED β-CELL FUNCTION VERSUS INSULIN RESISTANCE AS THE EARLIEST DEFECT

    As alluded to previously, people with IGT already have impaired β-cell function and insulin resistance although the reductions in β-cell function are approximately twice as great as those of insulin sensitivity. As shown in Fig. 2, in which both first- and second-phase insulin release are plotted as a function of insulin sensitivity, for any given degree of insulin resistance, each phase of insulin release is reduced in people with IGT. These data are not compatible with insulin resistance as the primary defect; if that were the case, one would expect to find greater β-cell function for a given degree of insulin resistance.

    Analyzing these data further in terms of individuals with and without a first-degree relative with type 2 diabetes (Table 2), we found that those with a first-degree relative with type 2 diabetes were comparably insulin resistant and had a comparable degree of impaired β-cell function for a comparable degree of glucose intolerance as indicated by HbA1c levels (5.59 ± 0.07 and 5.54 ± 0.07%). From these data, one cannot make any inferences regarding time of onset.

    However, comparison of individuals with normal glucose tolerance with and without a first-degree relative with type 2 diabetes does provide insight into this issue. As shown in Table 2, individuals with a first-degree relative with type 2 diabetes already have reductions in first- and second-phase insulin release while having no change in insulin sensitivity. This finding strongly suggests that impaired β-cell function precedes insulin resistance in those with a genetic predisposition to develop type 2 diabetes and thus that impaired β-cell function is the primary defect for type 2 diabetes.

    It has been argued that studies such as this include individuals who will not get type 2 diabetes. For such an argument to be a valid objection to the conclusions drawn, one would have to hypothesize that those not destined to get type 2 diabetes would have reduced β-cell function and better insulin sensitivity than those destined to get type 2 diabetes. From a common sense point of view, this hypothesis seems highly unlikely and is at variance with the results of studies of monozygotic twins discordant for type 2 diabetes.

    Given that the ultimate concordance rate for type 2 diabetes in monozygotic twins is >80%, one can infer that the monozygotic twin with normal glucose tolerance is a true prediabetic subject. There have been four studies of pairs of monozygotic twins in which one still has normal glucose (23–26). In all studies, evidence for impaired β-cell function has been found. In the only study (26) that simultaneously examined insulin sensitivity, insulin sensitivity was found not to be significantly reduced, whereas first-phase insulin release was reduced.

    DETERMINANTS OF THE FIRST AND SECOND PHASES OF INSULIN RELEASE AND INSULIN SENSITIVITY

    To further assess the genetic influence on β-cell function and insulin sensitivity, we examined the influence of family history of diabetes as well as other factors, such as age, sex, body weight, BMI, and waist-to-hip ratio, using multiple linear regression. As shown in Table 3, first phase and second phase were correlated with family history and BMI, the latter probably reflecting the influence of insulin resistance on β-cell function. First- and second-phase insulin release only differed in that age was negatively correlated with second-phase release. In contrast, insulin sensitivity was not correlated with a family history of diabetes but was with BMI and waist-to-hip ratio. These observations did not provide evidence for a major genetic influence on the insulin resistance associated with type 2 diabetes but do suggest that a major factor is excess body weight and its distribution. Of course, there is evidence that body fat and its distribution are under genetic control (29), but this would not represent a specific diabetes gene.

    CONCLUSIONS

    Based on the data presented above, a simple working model for the pathogenesis of type 2 diabetes is presented: certain individuals are born with genetically abnormal islets. This abnormality may be a reduced islet cell mass, accelerated apoptosis, susceptibility to amyloid toxicity, and other as yet undiscovered abnormalities. This genetic predisposition ultimately limits the ability to compensate for insulin resistance. Some individuals who remain lean and fit may never develop diabetes or may do so at a very old age because of progressive deterioration in β-cell function. In others who become insulin resistant because of weight gain, physical inactivity, high-fat diets, medications, etc., and are at risk of developing type 2 diabetes, age of onset and severity of diabetes will be determined by the balance between the ability of the β-cell to compensate and the degree of insulin resistance. This schema is consistent with the findings of abnormal β-cell function in individuals at high risk of developing type 2 diabetes on a genetic basis (i.e., the normoglycemic monozygotic twin of a patient with type 2 diabetes) (23–26) and the findings of the U.K. Prospective Diabetes Study (30) and Belfast Diet Study (31) demonstrating an ∼50% reduction in β-cell function at diagnosis of type 2 diabetes and subsequent further deterioration without an associated change in insulin sensitivity. Finally, this schema is consistent with therapeutic interventions aimed at preserving β-cell function/insulin secretion and at reducing the burden of insulin resistance.

    FIG. 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 1.

    Plasma glucose and insulin levels during hyperglycemic clamps. Reproduced with permission from Van Haeften et al. (20). FH, family history; NGT, normal glucose tolerance.

    FIG. 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    FIG. 2.

    Relationship between first- and second-phase insulin release and insulin sensitivity in subjects with normal glucose tolerance (NGT) and those with IGT. Reproduced with permission from Van Haeften et al. (20). LBM, lean body mass.

    View this table:
    • View inline
    • View popup
    TABLE 1

    Clinical characteristics of subjects

    View this table:
    • View inline
    • View popup
    TABLE 2

    Indexes of insulin secretion and insulin sensitivity in subjects with normal glucose tolerance (NGT) and IGT

    View this table:
    • View inline
    • View popup
    TABLE 3

    Partial correlation coefficients determined with multiple linear regression of baseline characteristics and parameters of insulin secretion and insulin sensitivity as estimated during hyperglycemic clamps

    Acknowledgments

    The present work was supported in part by National Institutes of Health/Division of Research Resources/General Clinical Research Centers Grants 5M01-RR00044 and NIDDK-20411.

    We wish to thank Mary Little for her superb editorial support.

    Footnotes

    • Address correspondence and reprint requests to johngerich{at}compuserve.com.

      Accepted for publication 30 May 2001.

      IGT, impaired glucose tolerance.

      The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.

    REFERENCES

    1. ↵
      Curry D, Bennett L, Grodsky G: Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83:572–584, 1968
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      Cerasi E, Luft R: What is inherited? What is added? Hypothesis for the pathogenesis of diabetes mellitus. Diabetes 16:615–627, 1967
      OpenUrlAbstract/FREE Full Text
    3. ↵
      Brunzell J, Robertson R, Lerner R, Hazzard W, Ensinck J, Bierman E, Porte D Jr: Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab 42:222–229, 1976
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      Kahn C, Soeldner J, Gleason R, Rojas L, Camerini-Davalos R, Marble A: Clinical and chemical diabetes in the offspring of diabetic couples. N Engl J Med 281:343–346, 1969
    5. ↵
      Gerich J: Metabolic abnormalities in impaired glucose tolerance. Metabolism 46:40–43, 1997
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J: Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29, 1992
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      Calles-Escandon J, Robbins D: Loss of early phase of insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose. Diabetes 36:1167–1172, 1987
      OpenUrlAbstract/FREE Full Text
    8. ↵
      Perley J, Kipnis D: Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46:1954–1962, 1967
    9. ↵
      Aitman T, Todd J: Molecular genetics of diabetes mellitus. Baillieres Clin Endocrinol Metab 9:631–656, 1995
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Iselius L, Lindsten J, Morton N, Efendic S, Cerasi E, Haegermark A, Luft R: Genetic regulation of the kinetics of glucose-induced insulin release in man. Clin Genet 28:8–15, 1985
      OpenUrlPubMedWeb of Science
    11. ↵
      Martin B, Warram J, Rosner B, Rich S, Soeldner J, Krolewski A: Familial clustering of insulin sensitivity. Diabetes 41:850–854, 1992
      OpenUrlAbstract/FREE Full Text
    12. ↵
      Bergman R, Phillips J, Cobelli C: Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and B-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1456–1467, 1981
    13. ↵
      Kahn S, Prigeon R, McCulloch D, Boyko E, Bergman R, Schwartz M, Neifing J, Ward W, Beard J, Palmer J, Porte D: Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects: evidence for a hyperbolic function. Diabetes 42:1663–1672, 1993
      OpenUrlAbstract/FREE Full Text
    14. ↵
      Pillay T, Langlois W, Olefsky J: The genetics of non-insulin-dependent diabetes mellitus. Adv Genet 32:51–98, 1995
      OpenUrlPubMed
    15. ↵
      Warram J, Martin B, Krolewski A, Soeldener S, Kahn C: Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909–915, 1990
    16. ↵
      Yki-Järvinen H: Glucose toxicity. Endocr Rev 13:415–431, 1992
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      Lee Y, Hirose H, Ohneda M, Johnson J, McGarry J, Unger R: Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A 91:10878–10882, 1994
      OpenUrlAbstract/FREE Full Text
    18. ↵
      Janson J, Ashley R, Harrison D, McIntyre S, Butler P: The mechanism of islet amyloid polypeptide toxicity is membrane disruptic by intermediate-sized toxic amyloid particles. Diabetes 48:491–498, 1999
      OpenUrlAbstract
    19. ↵
      Pimenta W, Kortytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J: Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA 273:1855–1861, 1995
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      Van Haeften T, Pimenta W, Mitrakou A, Korytkowski M, Jenssen T, Yki-Järvinen H, Gerich J: Relative contributions of β-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia. Metabolism 49:1318–1325, 2000
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      Van Haeften T, Dubbeldam S, Zonderland M, Erkelens D: Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects: assessments using hyperglycemic glucose clamps and oral glucose tolerance tests. Diabetes Care 21:278–282, 1998
      OpenUrlAbstract/FREE Full Text
    22. ↵
      Mitrakou A, Vuorinen-Markkola H, Raptis G, Toft I, Mokan M, Strumph P, Pimenta W, Veneman T, Jenssen T, Bolli G, Korytkowski M, Yki-Jarvinen H, Gerich J: Simultaneous assessment of insulin secretion and insulin sensitivity using a hyperglycemic clamp. J Clin Endocrinol Metab 75:379–382, 1992
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      Cerasi E, Luft R: Insulin response to glucose infusion in diabetic and nondiabetic monozygotic twin pairs: genetic control of insulin response. Acta Endocrinol 55:330–345, 1967
    24. Barnett A, Eff C, Leslie R, Pyke D: Diabetes in identical twins: a study of 200 pairs. Diabetologia 20:87–93, 1981
      OpenUrlCrossRefPubMedWeb of Science
    25. Pyke D, Taylor K: Glucose tolerance and serum insulin in unaffected identical twins of diabetics. BMJ 4:21–22, 1967
    26. ↵
      Vaag A, Henriksen J, Madsbad S, Holm N: Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 95:690–698, 1995
    27. Nyholm B, Mengel A, Nielsen S, Skjaerbaek C, Moller N, Alberti K, Schmitz O: Insulin resistance in relatives of NIDDM patients: the role of physical fitness and muscle metabolism. Diabetologia 39:813–822, 1996
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M: Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited: metabolic studies of offspring of diabetic probands. J Clin Invest 101:86–96, 1998
      OpenUrlPubMedWeb of Science
    29. ↵
      Bouchard C: Genetics and the metabolic syndrome. Int J Obes 19:S52–S59, 1995
      OpenUrl
    30. ↵
      UK Prospective Diabetes Study Group: UK Prospective Diabetes Study 16: overview of 6 year’s therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258, 1995
      OpenUrlAbstract/FREE Full Text
    31. ↵
      Levy J, Atkinson A, Bell P, McCance D, Hadden D: Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med 15:290–296, 1998
      OpenUrlCrossRefPubMedWeb of Science
    PreviousNext
    Back to top

    In this Issue

    February 2002, 51(suppl 1)
    • Table of Contents
    • Index by Author
    Sign up to receive current issue alerts
    View Selected Citations (0)
    Print
    Download PDF
    Article Alerts
    Sign In to Email Alerts with your Email Address
    Email Article

    Thank you for your interest in spreading the word about Diabetes.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Is Reduced First-Phase Insulin Release the Earliest Detectable Abnormality in Individuals Destined to Develop Type 2 Diabetes?
    (Your Name) has forwarded a page to you from Diabetes
    (Your Name) thought you would like to see this page from the Diabetes web site.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Citation Tools
    Is Reduced First-Phase Insulin Release the Earliest Detectable Abnormality in Individuals Destined to Develop Type 2 Diabetes?
    John E. Gerich
    Diabetes Feb 2002, 51 (suppl 1) S117-S121; DOI: 10.2337/diabetes.51.2007.S117

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    Add to Selected Citations
    Share

    Is Reduced First-Phase Insulin Release the Earliest Detectable Abnormality in Individuals Destined to Develop Type 2 Diabetes?
    John E. Gerich
    Diabetes Feb 2002, 51 (suppl 1) S117-S121; DOI: 10.2337/diabetes.51.2007.S117
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Jump to section

    • Article
      • Abstract
      • FIRST-PHASE VERSUS SECOND-PHASE INSULIN RELEASE
      • IMPAIRED β-CELL FUNCTION VERSUS INSULIN RESISTANCE AS THE EARLIEST DEFECT
      • DETERMINANTS OF THE FIRST AND SECOND PHASES OF INSULIN RELEASE AND INSULIN SENSITIVITY
      • CONCLUSIONS
      • Acknowledgments
      • Footnotes
      • REFERENCES
    • Figures & Tables
    • Info & Metrics
    • PDF

    Related Articles

    Cited By...

    More in this TOC Section

    • Clinical Characterization of Insulin Secretion as the Basis for Genetic Analyses
    • Effect of Acute Hyperglycemia on Insulin Secretion in Humans
    Show more Section 3: Phasic Insulin Release and Metabolic Control

    Similar Articles

    Navigate

    • Current Issue
    • Online Ahead of Print
    • Scientific Sessions Abstracts
    • Collections
    • Archives
    • Submit
    • Subscribe
    • Email Alerts
    • RSS Feeds

    More Information

    • About the Journal
    • Instructions for Authors
    • Journal Policies
    • Reprints and Permissions
    • Advertising
    • Privacy Policy: ADA Journals
    • Copyright Notice/Public Access Policy
    • Contact Us

    Other ADA Resources

    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • Scientific Sessions Abstracts
    • Standards of Medical Care in Diabetes
    • BMJ Open - Diabetes Research & Care
    • Professional Books
    • Diabetes Forecast

     

    • DiabetesJournals.org
    • Diabetes Core Update
    • ADA's DiabetesPro
    • ADA Member Directory
    • Diabetes.org

    © 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.