Role of Insulin Secretion and Sensitivity in the Evolution of Type 2 Diabetes in the Diabetes Prevention Program
Open accessAbstract
Insulin resistance and beta-cell dysfunction, two factors central to the pathogenesis of type 2 diabetes, were studied in relation to the development of diabetes in a group of participants with impaired glucose tolerance in the Diabetes Prevention Program (DPP) at baseline and after specific interventions designed to prevent diabetes. Participants were randomly assigned to placebo (n = 1,082), metformin (850 mg twice a day) (n = 1,073), or intensive lifestyle intervention (n = 1,079). The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio = 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity) and with baseline insulin secretion (hazard rate ratio = 0.57-0.76 per SD). Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio = 0.46-0.95 per SD increase and 0.29-0.79 per SD increase, respectively). In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables. The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of beta-cell function after 1 year, whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and beta-cell function after 1 year. In the metformin group, diabetes risk, insulin sensitivity, and beta-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups. In conclusion, higher insulin secretion and sensitivity at baseline and improvements in response to treatment were associated with lower diabetes risk in the DPP. The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of beta-cell function.
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Claims the paper makes
1 of 19 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Findingown data
Correlations between year 1 changes in metabolic variables were similar among treatment groups, except correlations between 1/fasting insulin and either CIR or IGR were higher in the metformin group.
“Correlations between the year 1 changes in metabolic variables were similar among the treatment groups, except for the correlations between 1/fasting insulin and either CIR or IGR, which were higher in the metformin group.”
Quote in the paperNot a substantial claim - Findingown data
Improvements in insulin secretion were associated with lower hazard rates for diabetes in all treatment arms (hazard rate ratio 0.46-0.95 per SD increase).
“Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio ؍ 0.46 -0.95 per SD increase and 0.29 -0.79 per SD increase, respectively).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
Hazard rates for developing diabetes were positively associated with baseline fasting plasma glucose, 120-min plasma glucose, and A1C.
“The hazard rates for developing diabetes were positively associated with baseline fasting plasma glucose, 120-min plasma glucose, and A1C (Fig. 3).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
In this large cohort of individuals with IGT, each variable (insulin sensitivity and insulin secretion) had an independent effect on the risk of developing diabetes.
“In this large cohort of individuals with IGT, our results clearly confirm this relationship because each variable had an independent effect on the risk of developing diabetes.”
Quote in the paperSubstantial claim - Findingown data
Fasting and 30- and 120-min glucose values decreased significantly in the lifestyle group.
“Fasting and 30-and 120-min glucose values decreased significantly in the lifestyle group”
Quote in the paperSubstantial claim
- Findingreasoning
With metformin, the decline in insulin secretory response was relatively less than the change in insulin sensitivity.
“this change was relatively less than the change in insulin sensitivity”
Quote in the paperSubstantial claim - Findingown data
The placebo group had no significant change in insulin sensitivity and β-cell function after 1 year.
“whereas the placebo group, which had the highest diabetes incidence, had no significant change in insulin sensitivity and -cell function after 1 year.”
Quote in the paperSubstantial claim - Findingown data
In DPP participants with impaired glucose tolerance, baseline insulin secretion was negatively associated with the hazard rate for developing diabetes (hazard rate ratio 0.57-0.76 per SD).
“and with baseline insulin secretion (hazard rate ratio ؍ 0.57-0.76per SD).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
In the lifestyle and placebo groups, hazard rates were negatively associated with baseline 1/fasting insulin.
“In the lifestyle and placebo groups, hazard rates were negatively associated with baseline 1/fasting insulin.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
Hazard rates for diabetes were positively associated with baseline weight in the lifestyle and placebo groups when adjusted for baseline demographics (age, sex, and race/ethnicity).
“The hazard rates for diabetes were positively associated with baseline weight in the lifestyle and placebo groups when adjusted for baseline demographics (age, sex, and race/ethnicity) (Fig. 4, left panels).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
Diabetes incidence was more strongly associated with baseline fasting glucose in the placebo group than in the others (P < 0.001).
“Diabetes incidence was more strongly associated with baseline fasting glucose in the placebo group than in the others (P Ͻ 0.001).”
Quote in the paperNot a substantial claim - Findingown data
In the lifestyle intervention and control groups, insulin sensitivity did not change significantly over 4 years.
“In the lifestyle intervention and control groups, insulin sensitivity did not change significantly over 4 years”
Quote in the paperNot a substantial claim - Findingcitation
In this large cohort of DPP participants at high risk for diabetes, fasting and 2-h OGTT glucose levels were positively associated with risk of progression to diabetes.
“This was also observed in this large cohort of DPP participants who were at high risk for diabetes.”
Quote in the paperNot a substantial claim - Findingown data
Improvements in insulin sensitivity were associated with lower hazard rates for diabetes in all treatment arms (hazard rate ratio 0.29-0.79 per SD increase).
“Improvements in insulin secretion and insulin sensitivity were associated with lower hazard rates in all treatment arms (hazard rate ratio ؍ 0.46 -0.95 per SD increase and 0.29 -0.79 per SD increase, respectively).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
In the metformin group, only fasting and 120-min glucose levels decreased.
“whereas in the metformin group, only fasting and 120-min glucose levels decreased.”
Quote in the paperNot a substantial claim - Findingown data
A beneficial effect of the intervention was indicated by an improvement in β-cell function over the 1st year of intervention.
“On the other hand, a beneficial effect of the intervention was indicated by an improvement in -cell function over the 1st year of intervention.”
Quote in the paperSubstantial claim - Findingown data
At the end of 4 years, insulin sensitivity tended to be greater in the lifestyle intervention group than in the control group.
“at the end of this period, it tended to be greater in the intervention group.”
Quote in the paperSubstantial claim - Findingown data
The relationship between insulin secretion and sensitivity was curved (i.e., linear on the log-log scale).
“In both comparisons, the relationship between insulin secretion and sensitivity was curved (i.e., linear on the log-log scale).”
Quote in the paperNot a substantial claim - Findingown data
With metformin, there was a small improvement in insulin sensitivity.
“With metformin, there was a small improvement in insulin sensitivity.”
Quote in the paperSubstantial claim - Findingown data
IGR and CIR were highly correlated at baseline (Spearman r = 0.95).
“IGR and CIR were highly correlated at baseline (Spearman r ϭ 0.95).”
Quote in the paperNot a substantial claim - Findingown data
The effects of both metformin and lifestyle in reducing the incidence of diabetes were associated with rightward shifts in the points representing median insulin secretion and sensitivity.
“The effects of both metformin and lifestyle in reducing the incidence of diabetes were associated with rightward shifts in the points representing median insulin secretion and sensitivity (Fig. 6, arrows)”
Quote in the paperSubstantial claim - Findingown data
The greatest reduction in glucose at year 1 occurred in the lifestyle group.
“The greatest reduction in glucose at year 1 occurred in the lifestyle group.”
Quote in the paperNot a substantial claim - Findingown data
With lifestyle intervention, the absolute insulin secretory response appears to have remained unchanged.
“the absolute insulin secretory response also appears to have remained unchanged.”
Quote in the paperSubstantial claim - Findingown data
In multivariate models that included changes in body weight, insulin sensitivity, and insulin secretion, each of the three variables significantly and independently predicted progression to diabetes when adjusted for the other two.
“In multivariate models that included the three metabolic variables (changes in body weight, insulin sensitivity, and insulin secretion) each significantly and independently predicted progression to diabetes when adjusted for the other two variables.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
The lifestyle intervention resulted in the greatest improvement in insulin sensitivity.
“The lifestyle intervention resulted in the greatest improvement in insulin sensitivity”
Quote in the paperSubstantial claim - Findingown data
Insulin secretion did not change in the lifestyle intervention group.
“Insulin secretion did not change in the lifestyle intervention group”
Quote in the paperSubstantial claim - Findingown data
Using either set of estimates, low insulin sensitivity and low insulin secretion at baseline predicted higher diabetes risk in all treatment arms.
“Using either set of estimates, low insulin sensitivity and low insulin secretion at baseline predicted higher diabetes risk in all treatment arms.”
Quote in the paperSubstantial claim - Findingown data
The diabetes risk reduction associated with lifestyle exceeded that with metformin by 37% (22-49%).
“The diabetes risk reduction associated with lifestyle exceeded that with metformin by 37% (22-49%).”
Quote in the paperSubstantial claim - Findingown data
In DPP participants with impaired glucose tolerance, baseline insulin sensitivity was negatively associated with the hazard rate for developing diabetes (hazard rate ratio 0.62-0.94 per SD difference, depending on treatment group and measure of sensitivity).
“The diabetes hazard rate was negatively associated with baseline insulin sensitivity (hazard rate ratio ؍ 0.62-0.94per SD difference, depending on treatment group and measure of sensitivity)”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
A greater improvement in either estimate of insulin sensitivity (1/fasting insulin or ISI) was associated with lower diabetes risk in all treatment arms.
“A greater improvement in either estimate of insulin sensitivity (1/fasting insulin or ISI) was also associated with lower diabetes risk in all treatment arms (Fig. 4F and H).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
An increase in estimated insulin secretion (CIR or IGR) predicted lower diabetes risk.
“Finally, an increase in estimated insulin secretion (CIR or IGR) also predicted lower diabetes risk (Fig. 4J and L).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
- Findingown data
Change in weight was an important factor, with greater weight loss translating to lower risk of developing diabetes.
“Interestingly, we found that change in weight was an important factor, with greater weight loss translating to lower risk.”
Quote in the paperSubstantial claim - Findingown data
Longitudinal analyses confirm that progressive loss of insulin secretion or worsening of insulin sensitivity was associated with greater diabetes risk.
“The longitudinal analyses (Fig. 4) confirm that progressive loss of insulin secretion or worsening of insulin sensitivity was associated with greater diabetes risk.”
Quote in the paperSubstantial claim - Findingown data
All partial correlations at baseline for glycemic indexes (fasting plasma glucose and A1C) with weight, fasting insulin, proinsulin, IGR, and CIR were significant in this large sample.
“All these correlations were significant in this large sample.”
Quote in the paperNot a substantial claim - Findingown data
Insulin secretion decreased significantly in the control group.
“but decreased significantly in the control group.”
Quote in the paperSubstantial claim - Findingown data
With metformin, the insulin secretory response appeared to decline in absolute terms.
“although the insulin secretory response appeared to decline in absolute terms”
Quote in the paperNot a substantial claim - Findingown data
When each treatment group was divided into tertiles of insulin sensitivity and secretion at baseline, those with the greatest risk of developing diabetes ranked in the lowest tertiles for both insulin sensitivity and secretion.
“Furthermore, when each treatment group was divided into tertiles of insulin sensitivity and secretion at baseline (Fig. 5), those with the greatest risk of developing diabetes ranked in the lowest tertiles for both insulin sensitivity and secretion.”
Quote in the paperSubstantial claim - Findingown data
In the metformin group, diabetes risk, insulin sensitivity, and β-cell function at 1 year were intermediate between those in the intensive lifestyle and placebo groups.
“In the metformin group, diabetes risk, insulin sensitivity, and -cell function at 1 year were intermediate between those in the intensive lifestyle and pla-cebo groups.”
Quote in the paperSubstantial claim - Findingnone given
There is a strong relationship between fasting proinsulin and fasting insulin levels.
“Because of the strong relationship between the fasting proinsulin and fasting insulin levels”
Quote in the paperSubstantial claim - Findingown data
Individuals who were most insulin resistant and had the poorest insulin secretory responses were at greatest risk of developing diabetes in the DPP.
“Those individuals who were most insulin resistant and had the poorest insulin secretory responses were at greatest risk of developing diabetes in the DPP.”
Quote in the paperSubstantial claim - Findingown data
The metabolic variables changed from baseline at a significance level of 0.05 for all metabolic variables except for weight in the placebo group.
“The metabolic variables changed from baseline at a significance level of 0.05 for all metabolic variables except for weight in the placebo group.”
Quote in the paperNot a substantial claim - Findingown data
All tests of mean changes over time between any two groups are statistically significant (P < 0.001) except in fasting glucose and fasting insulin between the lifestyle and metformin groups.
“All tests of mean changes over time between any two groups are statistically significant (P < 0.001) except in fasting glucose and fasting insulin between the lifestyle and metformin groups.”
Quote in the paperNot a substantial claim - Findingnone given
The magnitude of weight reduction was a predictor of a beneficial response to the intervention.
“the magnitude of weight reduction was a predictor of a beneficial response to the intervention”
Quote in the paperSubstantial claim - Findingown data
In time-dependent models using changes in metabolic variables from baseline up to but not including the values at the time of progression to diabetes, adjusted for baseline metabolic variable, baseline age, sex, and race/ethnicity, all changes in metabolic variables significantly predicted progression to diabetes.
“All changes in metabolic variables significantly predicted progression to diabetes (P ؍ 0.007 for IGR in the placebo group and P < 0.001 for the rest of the variables).”
Quote in the paperSubstantial claim - Findingreasoning
Higher proinsulin levels at baseline resulted in greater risk of progression to diabetes.
“with higher proinsulin levels at baseline resulting in the greater risk.”
Quote in the paperSubstantial claim - Findingown data
In separate models using baseline metabolic variables adjusted for baseline age, sex, and race/ethnicity, all baseline metabolic variables significantly predicted progression to diabetes in all treatment groups except for baseline weight and 1/fasting insulin in the metformin group.
“all baseline metabolic variables significantly predicted progression to diabetes in all treatment groups (P ؍ 0.016 in the metformin group for ISI and P < 0.001 for the rest of the variables) except for baseline weight and 1/fasting insulin in the metformin group.”
Quote in the paperSubstantial claim - Findingown data
Changes in insulin sensitivity and insulin secretion were independent predictors of a beneficial outcome.
“changes in insulin sensitivity and insulin secretion were also independent predictors of a beneficial outcome.”
Quote in the paperSubstantial claim - Findingown data
In separate models using baseline metabolic variables adjusted for baseline age, sex, and race/ethnicity, all three baseline metabolic variables significantly predicted progression to diabetes in all treatment groups (P < 0.001).
“In separate models using the baseline metabolic variables adjusted for baseline age, sex, and race/ethnicity, all three baseline metabolic variables significantly predicted progression to diabetes in all treatment groups (P < 0.001).”
Quote in the paperSubstantial claim - Premisecitation
A recently reported study demonstrated that a weight loss intervention in older individuals was associated with improved insulin sensitivity together with a relative preservation of the insulin response reflective of improved β-cell function.
“a recently reported study that demonstrated that a weight loss intervention in older individuals was associated with improved insulin sensitivity together with a relative preservation of the insulin response reflective of improved -cell function (31)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Utzschneider KM, Carr DB, Barsness SM, Kahn SE, Schwartz RS: Diet-induced weight loss is associated with an improvement in β-cell function in older men. J Clin Endocrinol Metab 89:2704–2710,2004 source
- Interpretationreasoning
In the lifestyle group, the changes in insulin sensitivity and secretion resulted in a rightward shift from the baseline curve, compatible with an enhancement of β-cell function relative to baseline.
“When relating insulin sensitivity to insulin secretion, the changes resulted in a rightward shift from the baseline curve and are compatible with an enhancement of -cell function relative to that at baseline (i.e., improved secretion relative to sensitivity).”
Quote in the paperSubstantial claim - Premisecitation
Fasting and 2-h OGTT glucose levels are positively associated with risk of progression to diabetes.
“It is well recognized that fasting and 2-h OGTT glucose levels are positively associated with risk of progression to diabetes (5).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF: Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 46:701–710,1997 source
- Premisecitation
The relationship between insulin sensitivity and insulin secretion is nonlinear.
“the known nonlinear relationship between these two variables (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Jr: Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. Diabetes 42:1663–1672,1993 source
- Interpretationreasoning
The relatively smaller decline in insulin secretory response compared with the change in insulin sensitivity with metformin suggests improved β-cell function.
“hence suggesting improved -cell function.”
Quote in the paperSubstantial claim- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
- Interpretationreasoning
The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of β-cell function.
“The better preventive effectiveness of intensive lifestyle may be due to improved insulin sensitivity concomitant with preservation of -cell function.”
Quote in the paperSubstantial claim - Study design and conductown data
There were no significant differences in any variables among the three intervention groups at baseline.
“There were no significant differences in any variables among the three intervention groups.”
Quote in the paperNot a substantial claim - Premisecitation
Insulin sensitivity is known to modulate insulin secretion.
“This relationship describes -cell function because insulin sensitivity is known to modulate insulin secretion (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Jr: Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. Diabetes 42:1663–1672,1993 source
- Interpretationreasoning
The rightward shifts associated with metformin and lifestyle are compatible with improved insulin sensitivity and β-cell function.
“compatible with improved insulin sensitivity and -cell function.”
Quote in the paperSubstantial claim- Rests on an assumption: The baseline relationship between insulin secretion and insulin sensitivity is the same across treatment groups.
- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
- Interpretationcitation
The DPP findings are consistent with the recently reported study of weight loss in older individuals.
“the DPP findings are also consistent with a recently reported study”
Quote in the paperNot a substantial claim - Interpretationreasoning
Changes in insulin secretion may reflect no change in β-cell function if the relationship between insulin response and insulin sensitivity remains the same, moving along the curve.
“The first would be compatible with no change in -cell function and would occur if changes in the insulin response and insulin sensitivity were such that the relationship remained the same.”
Quote in the paperSubstantial claim - Interpretationreasoning
The DPP findings provide a plausible mechanism by which lifestyle changes reduced the incidence of diabetes in other diabetes prevention studies.
“provide a plausible mechanism by which lifestyle changes reduced the incidence of diabetes in other diabetes prevention studies (32)(33)(34).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (32)(33)(34)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Fasting proinsulin levels increase with declining insulin sensitivity, probably as a result of increased secretory demand on the β-cell.
“As with fasting insulin, fasting proinsulin levels increase with declining insulin sensitivity, probably as a result of the increased secretory demand on the -cell (39).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Kahn SE, Leonetti DL, Prigeon RL, Bergstrom RW, Fujimoto WY: Proinsulin as a marker for the development of NIDDM in Japanese-American men. Diabetes 44:173–179,1995 source
- Interpretationreasoning
Proinsulin appeared to be a good marker of risk of progression to diabetes.
“proinsulin appeared to be a good marker of risk of progression to diabetes”
Quote in the paperSubstantial claim - Interpretationown data
Reduction in both insulin sensitivity and β-cell function underlie the progression from IGT to diabetes.
“reduction in both insulin sensitivity and -cell function underlie the progression from IGT to diabetes.”
Quote in the paperSubstantial claim- Rests on an assumption: The baseline relationship between insulin secretion and insulin sensitivity is the same across treatment groups.
- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
- May combine two claims. 24
- Classified as probably not a substantial claim. 7
May combine two claims.
PremisecitationImpaired fasting glycemia and impaired glucose tolerance are strong risk factors for type 2 diabetes.
“The latter two are strong risk factors for type 2 diabetes (1-6).”
Quote in the paperSubstantial claim1 of 6 sources checked- cites [1] The Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403,2002 source
- cites [2] Modan M, Karasik A, Halkin H, Fuchs Z, Lusky A, Shitrit A, Modan B: Effect of past and concurrent body mass index on prevalence of glucose intolerance and type 2 (non-insulin-dependent) diabetes and on insulin response: the Israel study of glucose intolerance, obesity and hypertension. Diabetologia 29:82–89,1986 source
The BMI INTERVAL section describes impaired glucose tolerance progressing to Type 2 diabetes, and the Discussion likewise describes worsening from impaired tolerance to diabetes. But the paper does not address impaired fasting glycemia or establish that both conditions are strong risk factors. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [3] Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH: The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 319:1500–1506,1988 source
- cites [4] Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-Jarvinen H, Freymond D, Nyomba BL, Zurlo F, Swinburn B, Bogardus C: Impaired glucose tolerance as a disorder of insulin action: longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318:1217–1225,1988 source
- cites [5] Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF: Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 46:701–710,1997 source
- cites [6] Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE, American Diabetes Association GENNID Study Group: β-Cell function is the major determinant of oral glucose tolerance in four ethnic groups in the United States. Diabetes 51:2170–2178,2002 source
May combine two claims.
Findingown dataAt 1 year, there was less reduction in fasting insulin in the metformin group than in the lifestyle group, with lifestyle participants having the greatest reduction throughout all years of follow-up.
“At 1 year, there was less reduction in fasting insulin in the metformin than in the lifestyle group, with the lifestyle participants having the greatest reduction throughout all years of follow-up.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataISI and 1/fasting insulin were highly correlated at baseline (Spearman r = 0.99).
“ISI and 1/fasting insulin were, as expected, highly correlated at baseline (Spearman r ϭ 0.99).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataWith additional follow-up data, the risk reductions (95% CI) of developing diabetes were 30% (16-41%) for metformin and 55% (45-63%) for lifestyle, each compared with placebo.
“Encompassing of the additional follow-up data yielded risk reductions (95% CI) of developing diabetes of 30% (16 -41%) for metformin and 55% (45-63%) for lifestyle, each compared with placebo.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA1C, proinsulin, insulin sensitivity, and insulin secretion also predicted the development of diabetes in these high-risk individuals.
“In addition, we found that A1C, proinsulin, insulin sensitivity, and insulin secretion also predicted the development of diabetes in these high-risk individuals.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong all participants, including those who developed diabetes, fasting glucose, insulin, and proinsulin concentrations were significantly lower than placebo at the first annual visit in the metformin and lifestyle groups and increased during the 2nd and 3rd years, with levels remaining significantly lower than in the placebo group.
“Among all participants, including those who developed diabetes, fasting glucose, insulin, and proinsulin concentrations were significantly lower than placebo at the first annual visit in the metformin and the lifestyle groups and increased during the 2nd and 3rd years, with the levels remaining significantly lower than in the placebo group (Fig. 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the placebo group, there was a significant increase in 30-min glucose and a significant decrease in 120-min glucose levels.
“In the placebo group, however, there was a significant increase in 30-min and a significant decrease in the 120-min glucose levels.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLifestyle and metformin treatments reduced the incidence of diabetes but did not change the independent effects of insulin sensitivity and secretion on the risk for diabetes; those with the lowest sensitivity and secretion within each treatment group still had the greatest risk, whereas those with the highest insulin sensitivity and secretion had uniformly low risk regardless of intervention group
“Whereas lifestyle and metformin treatments reduced the incidence of diabetes, they did not change the independent effects of insulin sensitivity and secretion on the risk for diabetes, so that those individuals with the lowest sensitivity and secretion within each treatment group still had the greatest risk, whereas those with the highest insulin sensitivity and secretion had uniformly low risk”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataChanges in weight and proinsulin over time were strong predictors of diabetes, with decreased weight and decreased proinsulin predicting a lower hazard of diabetes in all treatment arms.
“Changes in weight and proinsulin over time were strong predictors of diabetes, with decreased weight and decreased proinsulin predicting a lower hazard of diabetes in all treatment arms (Fig. 4B and D).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Hazard ratios were constant over time.
May combine two claims.
Findingown dataThe metformin group showed a more modest improvement in insulin sensitivity (ISI and 1/fasting insulin, P < 0.001) with a significant decrease in insulin secretion (IGR, P < 0.001).
“The metformin group showed a more modest improvement in insulin sensitivity (ISI and 1/fasting insulin, P Ͻ 0.001) with a significant decrease in insulin secretion (IGR, P Ͻ 0.001)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataImproved insulin sensitivity was associated with a decrease in the risk of developing diabetes, with the lifestyle intervention being the most effective.
“In addition, improved insulin sensitivity was also associated with a decrease in the risk of developing diabetes, with the lifestyle intervention again being the most effective.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the placebo group, there were no significant changes in either estimate of insulin sensitivity, a significant decrease in insulin secretion (IGR, P = 0.03), but no significant change in β-cell function.
“Finally, in the placebo group there were no significant changes in either estimate of insulin sensitivity, a significant decrease in insulin secretion (IGR, P ϭ 0.03) but no significant change in -cell function”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe intensive lifestyle intervention produced the greatest improvement in insulin sensitivity and the best preservation of β-cell function after 1 year.
“The intensive lifestyle intervention, which elicited the greatest reduction in diabetes incidence, produced the greatest improvement in insulin sensitivity and the best preservation of -cell function after 1 year”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe lifestyle group had the greatest improvement in insulin sensitivity (ISI and 1/fasting insulin, P < 0.001), and this was associated with a significant decrease in insulin secretion (IGR, P = 0.008).
“The lifestyle group had the greatest improvement in insulin sensitivity (ISI and 1/fasting insulin, P Ͻ 0.001), and this was associated with a significant decrease in insulin secretion (IGR, P ϭ 0.008).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the current data, the relationship between insulin secretion and insulin sensitivity was not hyperbolic but was well described as nonlinear.
“The relationships in the current data were not hyperbolic but were well described as nonlinear.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe risk of developing diabetes was lowest among participants in the lifestyle arm, intermediate among those assigned to metformin, and highest among placebo participants across the range of baseline glycemic variables.
“The risk of developing diabetes was lowest among participants in the lifestyle arm, intermediate among those assigned to metformin, and highest among placebo participants across the range of baseline glycemic variables.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTreatment effects on diabetes risk were seen regardless of categories of sensitivity and secretion, except in the lowest risk categories (high insulin sensitivity and secretion), in which hazard rates were uniformly low.
“In general, these treatment effects were seen regardless of the categories of sensitivity and secretion, except in the lowest risk categories (high insulin sensitivity and secretion), in which hazard rates were uniformly low.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe Diabetes Prevention Program found that the risk for developing type 2 diabetes was reduced by 58% in the intensive lifestyle group and 31% in the metformin-treated group compared with the placebo-treated group.
“found that the risk for developing type 2 diabetes was reduced by 58 and 31% in the intensive lifestyle and metformin-treated groups, respectively, compared with the placebo-treated group (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] The Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403,2002 source
May combine two claims.
InterpretationreasoningThese findings are compatible with lifestyle having the greatest effect to preserve β-cell function and being the more effective intervention to reduce the rate of development of diabetes.
“These findings are compatible, with lifestyle having the greatest effect to preserve -cell function and it being the more effective intervention to reduce the rate of development of diabetes.”
Quote in the paperSubstantial claim- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
Classified as probably not a substantial claim.
InterpretationreasoningChanges in insulin secretion may reflect decreased β-cell function if there is a shift to the left of or below the curve relating insulin sensitivity and insulin response.
“Finally, a decrease in -cell function would be characterized by a shift to the left of or below the curve.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoningβ-cell function was unchanged in the lifestyle intervention group while declining in the control group.
“Thus, it would appear that -cell function was unchanged in the lifestyle intervention group while declining in the control group.”
Quote in the paperSubstantial claim- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNinety-five percent of participants completed their first annual visit.
“Ninety-five percent of participants completed their first annual visit.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationA hyperbolic relationship between insulin secretion and insulin sensitivity has previously been described when more direct measures of insulin secretion and sensitivity were used.
“This hyperbolic relationship has previously been described when more direct measures of insulin secretion and sensitivity were used (29).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Jr: Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. Diabetes 42:1663–1672,1993 source
May combine two claims.
InterpretationreasoningLifestyle intervention and, to a lesser extent, metformin enhanced β-cell function and improved insulin sensitivity, leading to a reduced risk for developing diabetes.
“Lifestyle intervention and, to a lesser extent, metformin enhanced -cell function and improved insulin sensitivity, leading to a reduced risk for developing diabetes.”
Quote in the paperSubstantial claim- Rests on an assumption: The baseline relationship between insulin secretion and insulin sensitivity is the same across treatment groups.
- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
May combine two claims.
InterpretationreasoningWhereas change in body weight was a strong predictor of the risk of developing diabetes in the DPP, the interventions probably had differential effects on other variables or direct effects in the liver or muscle even after accounting for insulin secretion.
“Thus it appears that whereas change in body weight was a strong predictor of the risk of developing diabetes in the DPP, the interventions probably had differential effects on other variables or direct effects in the liver or muscle even after accounting for insulin secretion.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSimilar findings of the effect of lifestyle intervention have been reported for the Finnish Diabetes Prevention Study.
“Similar findings of the effect of lifestyle intervention have been reported for the Finnish Diabetes Prevention Study (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindström J, Tuomilehto J, Finnish Diabetes Prevention Study Group: Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes 52:2532–2538,2003 source
May combine two claims.
InterpretationreasoningIn the metformin group, the decrease in insulin secretion was not as large as might be expected from the concomitant change in insulin sensitivity, and therefore can be interpreted as improved secretion relative to sensitivity.
“but whereas the absolute response declined, this decrease was not as large as might be expected from the concomitant change in insulin sensitivity and therefore can be interpreted as improved secretion relative to sensitivity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe processing of proinsulin to insulin is never complete, so not all proinsulin molecules are cleaved, resulting in a small quantity of proinsulin being secreted along with insulin and C-peptide.
“this process is never complete so that not all proinsulin molecules are cleaved, resulting in a small quantity of proinsulin being secreted along with insulin and C-peptide (36 -38).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [36] Kitabchi AE: Proinsulin and C-peptide a review. Metabolism 26:547–587,1977 source
- cites [37] Mykkanen L, Haffner SM, Hales CN, Ronnemaa T, Laakso M: The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes 46:1990–1995,1997 source
- cites [38] Reaven GM, Chen Y-DI, Hollenbeck CB, Sheu WHH, Ostrega D, Polonsky KS: Plasma insulin, C-peptide, and proinsulin concentrations in obese and nonobese individuals with varying degrees of glucose tolerance. J Clin Endocrinol Metab 76:44–48,1993 source
May combine two claims.
InterpretationreasoningThe effect of metformin and intensive lifestyle in reducing the incidence of diabetes is related in part to their ability to shift the relationship between insulin sensitivity and insulin secretion in a direction compatible with an improvement in β-cell function, with lifestyle being more effective in doing so.
“The effect of metformin and intensive lifestyle in reducing the incidence of diabetes is related in part to their ability to shift the relationship between insulin sensitivity and insulin secretion in a direction compatible with an improvement in -cell function, with lifestyle being more effective in doing so.”
Quote in the paperSubstantial claim- Rests on an assumption: The baseline relationship between insulin secretion and insulin sensitivity is the same across treatment groups.
- Rests on an assumption: The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationProduction of insulin is dependent on the proteolytic processing in the β-cell secretory granule of proinsulin to insulin and C-peptide.
“production of insulin is dependent on the proteolytic processing in the -cell secretory granule of proinsulin to insulin and C-peptide (35).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Duckworth WC, Kitabchi AE, Heinemann M: Direct measurement of plasma proinsulin in normal and diabetic subjects. Am J Med 53:418–427,1972 source
The authors state this as an assumption.
Hazard ratios were constant over time.
“Hazard ratios were assumed to be constant over time.”
The paper relies on this without support.
Deterioration of either insulin sensitivity or insulin secretion is critical in determining the progression of hyperglycemia.
“Although the relative importance of decreased insulin sensitivity and insulin secretion in the pathogenesis of type 2 diabetes has been debated, it is generally accepted that deterioration of either or both is critical in determining the progression of hyperglycemia.”
The paper relies on this without support.
Insulin resistance and β-cell dysfunction are central characteristics of type 2 diabetes, impaired fasting glycemia, and impaired glucose tolerance.
“Insulin resistance and -cell dysfunction are two well-established characteristics of type 2 diabetes, impaired fasting glycemia, and impaired glucose tolerance (IGT).”
The paper relies on this without support.
The baseline relationship between insulin secretion and insulin sensitivity is the same across treatment groups.
“The curve represents the regression line of the logarithm of estimated insulin secretion as a linear function of the logarithm of estimated insulin sensitivity for all participants at baseline.”
The paper relies on this without support.
The three scenarios (no change, improvement, decrease in β-cell function) exhaustively characterize possible changes in the insulin secretion-sensitivity relationship.
“changes in insulin secretion may reflect one of three scenarios regarding -cell function.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the Diabetes Prevention Program, greater baseline β-cell function and insulin sensitivity contributed independently to the restoration of normal glucose tolerance following lifestyle changes.
“In the Diabetes Prevention Program (DPP), greater baseline β-cell function and insulin sensitivity contributed independently to the restoration of NGT following lifestyle changes ( 65 , 66 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [65]
The Results section ('Prediction of diabetes by multiple metabolic factors,' page not provided) reports that higher baseline insulin sensitivity and secretion were associated with lower diabetes risk, including in the lifestyle group. The Discussion (page not provided) says each had an independent effect on diabetes risk. The paper does not establish that these baseline measures independently contributed to restoration of normal glucose tolerance, which is a different outcome. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher diabetes incidence in all treatment groups was found among DPP individuals with lower measures of insulin secretory response at baseline.
“Indeed, higher diabetes incidence in all treatment groups was found among individuals with lower measures of insulin secretory response at baseline in the DPP (22).”
From Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes (2024) · cites this paper as [22]
Successful lifestyle interventions seem to improve insulin sensitivity and β-cell function.
“Successful lifestyle interventions seem to improve insulin sensitivity and β-cell function.92,93”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [93]
Insulin resistance could increase the risk of Alzheimer's disease through both cerebrovascular and amyloid-beta related mechanisms.
“Since insulin resistance could increase the risk of AD through both cerebrovascular and Aβ related mechanisms [23]”
From Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial (2016) · cites this paper as [23]
Large intervention studies with lifestyle interventions and drugs like metformin have shown that it is feasible to decrease hyperinsulinemia and the risk of diabetes.
“Large intervention studies with lifestyle interventions and drugs like metformin have shown that it is feasible to decrease hyperinsulinemia and the risk of diabetes (The Diabetes Prevention Program Research, 2005) and is possible that these interventions could extend to decreasing the risk of Alzheimer’s disease.”
From Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease (2008) · cites this paper as The Diabetes Prevention Program Research, 2005
Metformin reduces insulin levels, inflammation and thrombosis, and the risk of metabolic syndrome, and improves insulin sensitivity, suggesting its potential to exert protective effects on cognitive function.
“Studies showing that metformin (MET) not only reduces insulin levels (11), inflammation and thrombosis (12), and the risk of the metabolic syndrome (13), but also improves insulin sensitivity (11) suggests its potential to exert protective effects on cognitive function.”
From Type 2 Diabetes and Antidiabetic Medications in Relation to Dementia Diagnosis (2014) · cites this paper as [11]
The putative mechanisms of metformin's positive effects include reducing insulin levels and improving insulin sensitivity, reducing inflammation, and reducing the risk of metabolic syndrome.
“The putative mechanisms of MET's positive effects include (i) reducing insulin levels and improving insulin sensitivity (11), (ii) reducing inflammation (11), and (iii) reducing the risk of metabolic syndrome (25).”
From Type 2 Diabetes and Antidiabetic Medications in Relation to Dementia Diagnosis (2014) · cites this paper as [11]
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Prediabetes: a high-risk state for diabetes development
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Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction
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Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment
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Prediabetes and Cardiovascular Disease
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Hydroxychloroquine and Risk of Diabetes in Patients With Rheumatoid Arthritis
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“…of -cell function despite intensive therapy (Turner, 1998; UKPDS, 1998) individuals through enhancement of insulin sensitivity and -cell function (Kitabchi et al., 2005; Knowler et al., 2002) Diazoxide and other KATP channel openers - Opening of the KATP channel and inhibition of insulin…”
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Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention
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The prevention of type 2 diabetes
F. T. D. P. P. R. G., Crandall, J. P., Knowler, W. C., Kahn, S. E., Marrero, D., Florez, J. C., Bray, G. A., Haffner, S. M., Hoskin, M., & Nathan, D. M. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0843 · Cited by 261 · see citing works
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Glucose Intolerance in Pregnancy and Future Risk of Pre-Diabetes or Diabetes
Retnakaran, R. R., Qi, Y., Sermer, M., Connelly, P. W., Hanley, A. J., & Zinman, B. (2008) · Diabetes Care · doi:10.2337/dc08-0972 · Cited by 250 · see citing works
Preservation of β-Cell Function: The Key to Diabetes Prevention
DeFronzo, R. A., & Abdul-Ghani, M. A. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0246 · Cited by 247 · see citing works
Kahn, S. E., Lachin, J. M., Zinman, B., Haffner, S. M., Aftring, R. P., Paul, G., Kravitz, B. G., Herman, W. H., Viberti, G., Holman, R. R., et al. (2011) · Diabetes · doi:10.2337/db10-1392 · Cited by 249 · see citing works
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Incretin-Based Therapies in Type 2 Diabetes Mellitus
Chia, C. W., & Egan, J. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2109 · Cited by 221 · see citing works
β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
Halban, P. A., Polonsky, K. S., Bowden, D. W., Hawkins, M. A., Ling, C., Mather, K. J., Powers, A. C., Rhodes, C. J., Sussel, L., & Weir, G. C. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1425 · Cited by 228 · see citing works
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Adiposity, Type 2 Diabetes, and Alzheimer's Disease
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Type 2 Diabetes and Cognitive Impairment: Linking Mechanisms
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Aroda, V. R., Knowler, W. C., Crandall, J. P., Perreault, L., Edelstein, S. L., Jeffries, S., Molitch, M. E., Pi-Sunyer, X., Darwin, C. H., Heckman‐Stoddard, B. M., et al. (2017) · Diabetologia · doi:10.1007/s00125-017-4361-9 · Cited by 198 · see citing works
“Effects of metformin on diabetes prevention In 2002, the DPP published its primary findings from the masked-treatment phase, showing that the ILS and metformin groups had a respective 58% and 31% lower incidence of diabetes than the placebo group [2].”
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Protein intake and ovulatory infertility
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Wang, J., Kuusisto, J., Vänttinen, M., Kuulasmaa, T., Lindström, J., Tuomilehto, J. O., Uusitupa, M. I. J., & Laakso, M. (2007) · Diabetologia · doi:10.1007/s00125-007-0656-6 · Cited by 177 · see citing works
Brannick, B., Wynn, A., & Dagogo-Jack, S. E. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216654227 · Cited by 180 · see citing works
The RISE Consortium, Nadeau, K. J., Hannon, T. S., Edelstein, S. L., Arslanian, S. A., Caprio, S., Leschek, E. W., Zeitler, P. S., Buchanan, T. A., Ehrmann, D. A., et al. (2018) · Diabetes Care · doi:10.2337/dc18-0787 · Cited by 176 · see citing works
Cnop, M., Vidal, J., Hull, R. L., Utzschneider, K. M., Carr, D. B., Schraw, T., Scherer, P. E., Boyko, E. J., Fujimoto, W. Y., & Kahn, S. E. (2007) · Diabetes Care · doi:10.2337/dc06-1834 · Cited by 174 · see citing works
Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease
Luchsinger, J. A. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.02.048 · Cited by 171 · see citing works
Gestational Diabetes After Delivery
Kitzmiller, J. L., Dang-Kilduff, L., & Taslimi, M. M. (2007) · Diabetes Care · doi:10.2337/dc07-s221 · Cited by 174 · see citing works
TCF7L2 Polymorphisms Modulate Proinsulin Levels and β-Cell Function in a British Europid Population
Loos, R. J. F., Franks, P. W., Francis, R. W., Barroso, I., Gribble, F. M., Savage, D. B., Ong, K. K., O’Rahilly, S., & Wareham, N. J. (2007) · Diabetes · doi:10.2337/db07-0055 · Cited by 169 · see citing works
Adiposity and Alzheimer's disease
Luchsinger, J. A., & Gustafson, D. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e32831c8c71 · Cited by 170 · see citing works
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Adiponectin, Change in Adiponectin, and Progression to Diabetes in the Diabetes Prevention Program
Mather, K. J., Funahashi, T., Matsuzawa, Y., Edelstein, S. L., Bray, G. A., Kahn, S. E., Crandall, J. P., Marcovina, S. M., Goldstein, B., Goldberg, R. B., et al. (2008) · Diabetes · doi:10.2337/db07-1419 · Cited by 160 · see citing works
“Insulin sensitivity was assessed using inverse fasting insulin levels, as in our prior publications (28).”
MethodAdherence to Preventive Medications
Walker, E. A., Molitch, M., Kramer, M. K., Kahn, S., Ma, Y., Edelstein, S., Smith, K., Johnson, M. K., Kitabchi, A., Crandall, J., et al. (2006) · Diabetes Care · doi:10.2337/dc06-0454 · Cited by 161 · see citing works
Cárdenas, A., Gold, D. R., Hauser, R. B., KLEINMAN, K. P., Hivert, M., Calafat, A. M., Ye, X., Webster, T. F., Horton, E. S., & Oken, E. (2017) · Environmental Health Perspectives · doi:10.1289/ehp1612 · Cited by 146 · see citing works
“As previously demonstrated in the DPP, the e ff ect of the life-style intervention was strongly associated with diabetes incidence and had a large in fl uence on metabolic and glycemic markers over time (Kitabchi et al. 2005).”
Statin use and risk of developing diabetes: results from the Diabetes Prevention Program
Crandall, J. P., Mather, K., Rajpathak, S. N., Goldberg, R. B., Watson, K., Foo, S., Ratner, R., Barrett-Connor, E., & Temprosa, M. (2017) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2017-000438 · Cited by 137 · see citing works
Cefalu, W. T., Buse, J. B., Tuomilehto, J. O., Fleming, G. A., Ferrannini, E., Gerstein, H. C., Bennett, P. H., Ramachandran, A., Raz, I., Rosenstock, J., et al. (2016) · Diabetes Care · doi:10.2337/dc16-0873 · Cited by 143 · see citing works
Gong, X., Ji, M., Xu, J., et al. (2019) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2019.1634517 · Cited by 141 · see citing works
Diabetes Prevention Program Research Group (2015) · Diabetes Care · doi:10.2337/dc14-0886 · Cited by 139 · see citing works
Florez, J. C., Jablonski, K. A., Sun, M. W., Bayley, N., Kahn, S. E., Shamoon, H., Hamman, R. F., Knowler, W. C., Nathan, D. M., & Altshuler, D. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2275 · Cited by 131 · see citing works
Yoon, U., Kwok, L. L., & Magkidis, A. (2012) · Metabolism · doi:10.1016/j.metabol.2012.07.009 · Cited by 129 · see citing works
Detweiler-Bedell, J. B., Friedman, M. A., Leventhal, H., Miller, I. W., & Leventhal, E. A. (2008) · Clinical Psychology Review · doi:10.1016/j.cpr.2008.09.002 · Cited by 125 · see citing works
Florez, J. C., Jablonski, K. A., Kahn, S. E., Franks, P. W., Dabelea, D., Hamman, R. F., Knowler, W. C., Nathan, D. M., & Altshuler, D. (2007) · Diabetes · doi:10.2337/db06-0966 · Cited by 119 · see citing works
Inflammation and schizophrenia
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Body Size and Shape Changes and the Risk of Diabetes in the Diabetes Prevention Program
Fujimoto, W. Y., Jablonski, K. A., Bray, G. A., Kriska, A. M., Barrett-Connor, E. L., Haffner, S. M., Hanson, R. L., Hill, J. O., Hubbard, V. S., Stamm, E. R., et al. (2007) · Diabetes · doi:10.2337/db07-0009 · Cited by 117 · see citing works
Fowler, S. P. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.04.047 · Cited by 117 · see citing works
Ehrmann, D. A., Temple, K. A., Rue, A., Barengolts, E., Mokhlesi, B., Cauter, E. V., Sam, S., Miller, M. A., Kahn, S. E., Atkinson, K. M., et al. (2018) · Diabetes Care · doi:10.2337/dc18-0243 · Cited by 119 · see citing works
Lorenzo, C., Wagenknecht, L. E., Agostino, R. B. D., Rewers, M., Karter, A. J., & Haffner, S. M. (2009) · Diabetes Care · doi:10.2337/dc09-1115 · Cited by 116 · see citing works
Anti-Diabetic Effect of Portulaca oleracea L. Polysaccharideandits Mechanism in Diabetic Rats
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Lachin, J. M., Christophi, C. A., Edelstein, S. L., Ehrmann, D. A., Hamman, R. F., Kahn, S. E., Knowler, W. C., Nathan, D. M., & on behalf of the DPP Research Group (2007) · Diabetes · doi:10.2337/db06-0918 · Cited by 107 · see citing works
Prevention of Diabetes With Pioglitazone in ACT NOW
DeFronzo, R. A., Tripathy, D., Schwenke, D. C., Banerji, M., Bray, G. A., Buchanan, T. A., Clement, S. C., Gastaldelli, A., Henry, R. R., Kitabchi, A. E., et al. (2013) · Diabetes · doi:10.2337/db13-0265 · Cited by 109 · see citing works
Metformin, beyond an insulin sensitizer, targeting heart and pancreatic β cells.
Yang, X., Xu, Z., Zhang, C., Cai, Z.-X., & Zhang, J.-J. (2017) · Biochimica et Biophysica Acta - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.09.019 · Cited by 102 · see citing works
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A preclinical overview of metformin for the treatment of type 2 diabetes
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A cross-sectional study of vitamin D and insulin resistance in children
Kelly, A. T., Brooks, L. J., Dougherty, S., Carlow, D. C., & Zemel, B. S. (2011) · Archives of Disease in Childhood · doi:10.1136/adc.2010.187591 · Cited by 100 · see citing works
Fritsche, A., Wagner, R. J., Heni, M., Kantartzis, K., Machann, J., Schick, F., Lehmann, R., Peter, A., Dannecker, C., Fritsche, L., et al. (2021) · Diabetes · doi:10.2337/db21-0526 · Cited by 102 · see citing works
The RISE Consortium (2013) · Diabetes Care · doi:10.2337/dc13-1879 · Cited by 101 · see citing works
Lifestyle intervention for prevention of diabetes: determinants of success for future implementation
Roumen, C., Blaak, E. E., & Corpeleijn, E. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.2009.00181.x · Cited by 95 · see citing works
Goldberg, R. B., Temprosa, M. G., Haffner, S. M., Orchard, T. J., Ratner, R. E., Fowler, S. E., Mather, K. J., Marcovina, S. M., Saudek, C. D., Matulik, M. J., et al. (2009) · Diabetes Care · doi:10.2337/dc08-0494 · Cited by 91 · see citing works
Retnakaran, R. R., Qi, Y., Sermer, M., Connelly, P. W., Zinman, B., & Hanley, A. J. (2008) · Diabetes Care · doi:10.2337/dc08-0126 · Cited by 91 · see citing works
“In pregnant women, ISOGTT exhibits better correlation with insulin sensitivity measured by euglycemic-hyperinsulinemic clamp than either homeostasis model assessment of insulin resistance (HOMA-IR) or quantitative insulin sensitivity check in- dex (12).”
MethodInfluentialSatoh, H., Ohira, T., Hosoya, M., Sakai, A., Watanabe, T., Ohtsuru, A., Kawasaki, Y., Suzuki, H., Takahashi, A., Kobashi, G., et al. (2015) · Journal of Diabetes Research · doi:10.1155/2015/627390 · Cited by 91 · see citing works
“Intensive lifestyle interventionwas more effective than medication in slowing the progression to diabetes, partially due to the fact that lifestyle modifications provide greater improvements in insulin sensitivity andβ-cell functions [9].”
Hanley, A. J., Retnakaran, R. R., Qi, Y., Gerstein, H. C., Perkins, B. A., Raboud, J., Harris, S. B., & Zinman, B. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0719 · Cited by 90 · see citing works
Endothelial dysfunction, ADMA and insulin resistance in essential hypertension
Perticone, F., Sciacqua, A., Maio, R., Perticone, M., Leone, G. G., Bruni, R., Cello, S. D., Pascale, A., Talarico, G., Greco, L., et al. (2009) · International Journal of Cardiology · doi:10.1016/j.ijcard.2008.12.131 · Cited by 88 · see citing works
Diabetes, related conditions, and dementia
Luchsinger, J. A. (2010) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2010.08.063 · Cited by 86 · see citing works
Hofsø, D., Jenssen, T. G., Bollerslev, J., Ueland, T., Godang, K., Stümvoll, M., Sandbu, R., Røislien, J., & Hjelmesaeth, J. S. (2010) · European Journal of Endocrinology · doi:10.1530/eje-10-0804 · Cited by 83 · see citing works
Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot
Liao, W., Xu, J., Li, B., Ruan, Y., Li, T., & Liu, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.728315 · Cited by 84 · see citing works
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Can New-Onset Diabetes After Kidney Transplant Be Prevented?
Chakkera, H. A., Weil, E. J., Pham, P. T., Pomeroy, J. J., & Knowler, W. C. (2013) · Diabetes Care · doi:10.2337/dc12-2067 · Cited by 80 · see citing works
Metformin for treatment of antipsychotic-induced weight gain: A randomized, placebo-controlled study
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“A variety of data indicate that insulin resistance plays a central role in the development of diabetes and other metabolic disturbances (Kitabchi et al., 2005; Semenkovich, 2006).”
BackgroundExercise and diabetes: relevance and causes for response variability
Böhm, A., Weigert, C., Staiger, H., & Häring, H. (2015) · Endocrine · doi:10.1007/s12020-015-0792-6 · Cited by 79 · see citing works
ß‐cell function and anti‐diabetic pharmacotherapy
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The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes
Patterson, R. E., Marinac, C. R., Sears, D. D., Kerr, J., Hartman, S. J., Cadmus‐Bertram, L., Villaseñor, A., Flatt, S. W., Godbole, S. V., Li, H., et al. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy040 · Cited by 77 · see citing works
Gradmark, A., Pomeroy, J. J., Renström, F., Steiginga, S., Persson, M., Wright, A., Bluck, L. J. C., Domellöf, M., Kahn, S. E., Mogren, I., et al. (2011) · BMC Pregnancy and Childbirth · doi:10.1186/1471-2393-11-44 · Cited by 76 · see citing works
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“Recently, a nonlinear function describing the relationship between the oral glucose–induced early insulin response and insulin sensitivity has been used to assess b-cell function in both observational (18) and interventional studies in adults (19).”
Metformin, lifestyle intervention, and cognition in the Diabetes Prevention Program Outcomes Study
Luchsinger, J. A., Ma, Y., Christophi, C. A., Florez, H., Golden, S. H., Hazuda, H., Crandall, J., Venditti, E., Watson, K., Jeffries, S., et al. (2017) · Diabetes Care · doi:10.2337/dc16-2376 · Cited by 75 · see citing works
Serván, P. R. (2013) · PubMed · doi:10.3305/nh.2013.28.sup5.6929 · Cited by 74 · see citing works
“Improvements in insulin sensitivity and insulin secretion, greatest in the intensive lifestyle intervention group, and somewhat lower in the metformin group, correlated directly with decreased risk of diabetes.(18) Lifestyle intervention may also be effective in individuals without impaired glucose tolerance in the MR…”
BackgroundPorter, K. M., Ward, M., Hughes, C., O’Kane, M., Hoey, L., McCann, A., Molloy, A. M., Cunningham, C. J., Casey, M. C., Tracey, F., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01791 · Cited by 74 · see citing works
The RISE Consortium, Ehrmann, D. A., Temple, K. A., Rue, A., Barengolts, E., Mokhlesi, B., Van Cauter, E., Sam, S., Miller, M. A., Kahn, S. E., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0556 · Cited by 73 · see citing works
- Authors
- The Diabetes Prevention Program Research Group
- Affiliations
- George Washington University (US)
- Corresponding author
- The Diabetes Prevention Program Research Group
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-08-01
- Volume
- 54
- Issue
- 8
- Pages
- 2404-2414
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC1360738
- OpenAlex
- W11872906
- Semantic Scholar
- 325f16dd65ffe228accc202bdf7b70e715176447
- Cited by
- 446
- References
- 49
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 16 · 2023: 19 · 2022: 14 · 2021: 19 · 2020: 19 · 2019: 18 · 2018: 22 · 2017: 17 · 2016: 26 · 2015: 24 · 2014: 26 · 2013: 17 · 2012: 31
- FWCI
- 16.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- Bristol-Myers Squibb
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Institute on Aging
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)
- National Institute of Child Health and Human Development
- National Center for Research Resources
- Office of Women's Health
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 2 diabetes prevention, insulin secretion, insulin sensitivity, insulin resistance, beta-cell dysfunction, impaired glucose tolerance, metformin, intensive lifestyle intervention, Diabetes Prevention Program, diabetes incidence, weight change
- MeSH terms
- Insulin Secretion, Adult, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Tolerance Test, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Islets of Langerhans, Life Style, Male, Metformin, Middle Aged, Placebos
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