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. Author manuscript; available in PMC: 2023 Oct 4.
Published in final edited form as: Cell Metab. 2022 Sep 8;34(10):1431–1441.e5. doi: 10.1016/j.cmet.2022.08.012

Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes

Mihoko Yoshino 1, Jun Yoshino 1,4, Gordon I Smith 1, Richard I Stein 1, Adam J Bittel 2, Daniel C Bittel 2, Dominic N Reeds 1, David R Sinacore 2,5, W Todd Cade 2, Bruce W Patterson 1, Kevin Cho 3, Gary J Patti 3, Bettina Mittendorfer 1, Samuel Klein 1,6,7
PMCID: PMC9728552  NIHMSID: NIHMS1832259  PMID: 36084645

SUMMARY

Lifestyle therapy (energy-restriction and exercise) is the cornerstone of therapy for people with type 2 diabetes (T2D) but is difficult to implement. We conducted an 8-month randomized controlled trial in persons with obesity and T2D (17 women and 1 man) to determine the therapeutic effects and potential mechanisms of intensive lifestyle therapy on cardiometabolic function. Intensive lifestyle therapy was conducted at the worksite to enhance compliance and resulted in marked (17%) weight loss, and beneficial changes in body fat mass, intrahepatic triglyceride content, cardiorespiratory fitness, muscle strength, glycemic control, β-cell function and multi-organ insulin sensitivity, which were associated with changes in muscle NAD+ biosynthesis, sirtuin signaling, and mitochondrial function and in adipose tissue remodeling. These findings demonstrate that intensive lifestyle therapy provided at the worksite has profound therapeutic clinical and physiological effects in people with T2D, that are likely mediated by specific alterations in skeletal muscle and adipose tissue biology.

eTOC Blurb

⦁ Mihoko et al. report that intensive lifestyle therapy provided at the worksite causes marked weight loss, increased cardiorespiratory fitness and muscle strength, and improved physiological factors involved in the pathogenesis of T2D (β-cell function, multi-organ insulin sensitivity, and skeletal muscle/adipose tissue biology) in people with obesity and type 2 diabetes

Graphical Abstract

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INTRODUCTION

The increase in the prevalence of obesity in the last several decades has led to a marked increase in the prevalence of type 2 diabetes (T2D). Accordingly, T2D has become a major global public health problem because of its causal relationship with serious medical complications, adverse effects on physical function, and considerable economic impact related to increased healthcare costs and decreased productivity (American Diabetes Association, 2018; Manuel and Schultz, 2004; Seuring et al., 2015; Wild et al., 2004). Lifestyle therapy that involves decreasing dietary energy intake and increasing physical activity with concomitant weight loss is the cornerstone of treatment for patients with obesity and T2D (American Diabetes Association, 2020). Weight loss has a dose-dependent therapeutic effect on metabolic function and glycemic control in people with prediabetes and T2D (Magkos et al., 2016; Wing et al., 2011). Moreover, diabetes remission (HbA1c <6.5% without diabetes medications (Riddle et al., 2021) often occurs after 15%−20% weight loss in those who do not have longstanding T2D or severe β-cell dysfunction (Dixon et al., 2008; Lean et al., 2018; Yoshino et al., 2020). Regular exercise, particularly the combination of endurance and resistance exercise, is an important component of lifestyle therapy in people with T2D because it has therapeutic effects on glycemic control that are independent of weight loss (Boule et al., 2001; Church et al., 2010; Sigal et al., 2007).

Providing an effective lifestyle intervention is often challenging because of limited availability of evidence-based programs, high cost, and participant inconvenience. A worksite setting provides a unique opportunity for lifestyle therapy because it can reduce or eliminate many of these barriers and further enhance compliance by providing social support associated with a group setting. Although a systematic review of worksite-based weight loss programs and subsequent individual studies found worksite interventions resulted in only modest weight loss and no program achieved the large weight loss needed to induce diabetes remission (Almeida et al., 2015; Benedict and Arterburn, 2008; Kramer et al., 2015), most interventions in these studies were of low or moderate intensity and provided minimal supervision (contact less than once per month), and only one program included supervised exercise sessions. We are not aware of any studies that evaluated the potential therapeutic effect of an intensive diet and supervised exercise intervention conducted at a worksite setting.

The purpose of the present study was to conduct an 8-month randomized, controlled trial in people with obesity and T2D to determine the therapeutic effects of intensive lifestyle therapy (ILT) that involved both dietary energy restriction and supervised exercise training conducted at the worksite compared to standard care (dietary and physical activity instructions as recommended by the American Diabetes Association (ADA) guidelines (American Diabetes Association, 2020)) on: i) the major factors involved in the pathogenesis of T2D (insulin sensitivity, β-cell function and the metabolic response to glucose ingestion); ii) body composition; iii) physical function (cardiorespiratory fitness and muscle strength); iv) plasma concentrations of adipokines that could influence insulin action (adiponectin and plasminogen activator inhibitor-1 [PAI-1]); and v) potential cellular mechanisms purported to affect insulin action (skeletal muscle gene expression profile and mitochondrial function, and adipose tissue expression of genes involved in extracellular matrix [ECM] formation and inflammation). We hypothesized that the improvement in whole-body insulin sensitivity (primary outcome) and all of the major factors involved in the pathogenesis of T2D (secondary outcomes) would be much greater in the ILT than the SC group.

RESULTS

Study flow and compliance

Eight participants in the SC group (all women, age: 49.6 ± 11.4 years; 6.3 ± 5.8 years since T2D diagnosis) and 10 participants in the ILT group (9 women and 1 man; age: 53.5 ± 6.4 years; 6.1 ± 4.9 years since T2D diagnosis) completed the study (Figure S1). Participants in the ILT group attended 98 ± 4% of the weekly dietary and behavioral sessions and 92 ± 7% of the supervised exercise training sessions. A measure of dietary intake was obtained by averaging 24-h dietary recall data obtained on 2–4 occasions before and at the end of the study in the SC and ILT groups. Energy, carbohydrate and fat intake decreased in the ILT group but did not change in the SC group, and there were no changes in protein, fiber or cholesterol intake in either group (Table S1). By using the National Institute of Diabetes and Digestive and Kidney Diseases body weight planner (https://www.niddk.nih.gov/bwp), we estimated that a mean daily energy deficit of ~500 kcal was required in the ILT group to achieve the weight loss observed during the 8-month intervention. This calculated energy deficit was consistent with the self-reported decrease in energy intake.

Body composition and selected metabolic variables

Body weight, fat-free mass (FFM), total body fat mass, appendicular lean mass, intra-abdominal adipose tissue volume, and intrahepatic triglyceride content did not change in the standard care (SC) group (Table 1 and Figures S2 and S3). Participants in the ILT group lost 17.4 ± 6.6% of their initial body weight (range 6.4% to 28.6%, Figure S3), which was associated with marked reductions in total body fat mass, intra-abdominal adipose tissue volume, and intrahepatic triglyceride content (34 ± 12%, 39 ± 18%, and 63 ± 28% reductions from baseline, respectively; all P < 0.001, ILT vs SC), but no change in FFM or appendicular lean mass (Table 1 and Figures S2 and S3). Plasma triglyceride concentration decreased after ILT, but did not change after SC (P = 0.009, ILT vs SC), and there was no change in plasma HDL-cholesterol after ILT or SC (Table 1). Plasma PAI-1 concentration decreased after ILT, but not SC (P < 0.001, ILT vs SC), and plasma adiponectin concentration did not change in either the ILT or SC group (Table 1).

Table 1.

Body composition and metabolic variables before and after Standard Care or Intensive Lifestyle Therapy

Standard Care (n=8) Intensive Lifestyle Therapy (n=10)
Before After Before After PANCOVA
Body weight (kg) 95.9 ± 11.4 95.0 ± 11.8 96.1 ± 24.3 79.7 ± 23.0* <0.001
Body mass index (kg/m2) 37.5 ± 5.0 37.1 ± 4.8 37.2 ± 6.3 30.8 ± 6.1* <0.001
Fat mass (kg) 45.5 ± 8.2 44.7 ± 7.5 45.3 ± 10.4 30.2 ± 9.9* <0.001
Body fat (%) 47.5 ± 3.3 47.5 ± 3.9 47.7 ± 2.9 37.5 ± 3.4* <0.001
Fat free mass (kg) 50.0 ± 4.6 49.1 ± 5.1 50.2 ± 14.8 49.7 ± 14.0 0.622
Appendicular lean mass (kg) 21.7 ± 2.2 21.5 ± 2.3 21.0 ± 6.9 20.8 ± 7.4 0.865
Intra-abdominal adipose tissue volume (cm3)a 1,404 ± 483 1,393 ±576 1,789 ± 567 1,122 ± 591* 0.001
Intrahepatic triglyceride content (%)a 13.5 ± 9.0 12.9 ± 8.3 13.8 ± 7.5 3.7 ± 1.7* <0.001
Triglyceride (mg/dL) 125 ± 59 121 ± 66 148 ± 77 86 ± 28* 0.009
HDL-cholesterol (mg/dL) 44 ± 12 44 ± 8 50 ± 14 53 ± 12 0.055
Fasting glucose (mmol/L) 8.9 ± 1.1 8.5 ± 1.0 8.3 ± 1.7 6.0 ± 1.7* <0.001
Fasting insulin (pmol/L) 98 ± 28 94 ± 23 79 ± 39 44 ± 24* <0.001
Basal ISR (pmol/min) 229 ± 67 232 ± 59 230 ±129 171 ± 68 0.012
Basal ICR (L/min) 2.5 ± 0.9 2.6 ± 0.9 3.0 ± 1.0 4.3 ± 1.9* 0.024
HbA1c (%) 7.6 ± 1.1 8.0 ± 1.7 7.0 ± 1.1 6.1 ± 0.9* 0.015
Medication Score 0.96 ± 0.67 0.98 ± 0.69 0.79 ± 0.73 0.40 ± 0.58* 0.005
Adiponectin (mg/L) 5.3 ± 1.4 5.6 ± 1.8 9.4 ± 7.1 8.9 ± 4.8 0.389
PAI-1 (pg/L) 159 ± 75 173± 131 176 ± 99 47 ± 22* <0.001
Total 1RM (kg)b 214 ± 28 222 ± 31 215 ± 30 271 ± 32* 0.003
Peak oxygen consumption (mL/kg FFM/min) 32.2 ± 6.2 31.4 ± 6.8 33.8 ± 5.8 42.4 ± 4.6* 0.001
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Data are means ± SD. Analysis of covariance (ANCOVA) was used to determine the significance of differences between groups after the intervention, adjusted for the Before intervention value.

a

Standard Care, n=7; Intensive Lifestyle Therapy, n=10.

b

Standard Care, n=7; Intensive Lifestyle Therapy, n=9.

*

Value significantly different from corresponding Before value by Student’s t-tests for paired samples, P < 0.05. Abbreviations: Total 1RM, total one repetition maximum assessed as sum of the maximum weight lifted in the leg press, bench press, seated row, and knee flexion exercises; FFM, fat free mass; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; PAI-1, plasminogen activator inhibitor-1; ISR, insulin secretion rate; ICR, insulin clearance rate.

Muscle strength and cardiorespiratory fitness

Muscle strength, assessed as the total maximal weight lifted during 1 repetition maximum (1RM) tests for leg press, knee flexion, seated row, and chest press, did not change in the SC group but increased by 28 ± 20% in the ILT group (P = 0.003, ILT vs SC) (Table 1). Cardiorespiratory fitness, assessed as peak oxygen consumption per kg FFM during cycle ergometer exercise, did not change in the SC group but increased by 28 ± 22% in the ILT group (P = 0.001, ILT vs SC) (Table 1).

Glycemic control and metabolic response to glucose ingestion

Fasting plasma glucose and insulin concentrations, hemoglobin A1c (HbA1c) and diabetes medication score did not change in the SC group, but fasting plasma glucose, insulin concentration and HbA1c decreased in the ILT group even though there was a 61 ± 31% decrease in the diabetes medication score (Table 1). The decrease in fasting plasma insulin concentration after ILT was primarily due to an increase in insulin clearance rate (ICR) but also a decrease in insulin secretion rate (ISR) (Table 1). Three participants in the ILT group, but none in the SC group, achieved remission of T2D, defined as HbA1c <6.5% without the use of diabetes medications (Riddle et al., 2021). The 5-hour postprandial areas under the curve (AUC0–300) for plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) did not change after SC, but decreased by ~20% (P < 0.001, ILT vs SC) and ~25% (P < 0.01, ILT vs SC), respectively, in the ILT group (Table 2 and Figures 1A, 1B). Endogenous glucose production rate during the OGTT (AUC0–300) did not change in the SC group, but decreased by ~30% in the ILT group (P < 0.05 after vs before) (Table 2 and Figure 1G).

Table 2.

Metabolic response to glucose ingestion before and after Standard Care or Intensive Lifestyle Therapy

Standard Care Intensive Lifestyle Therapy
Before After Before After PANCOVA
Glucose AUC0–300 (mmol/L × min × 103) 4.0 ± 0.5 4.1 ± 0.6 3.9 ± 0.9 3.1 ± 0.8* <0.001
Insulin AUC0–300 (pmol/L × min × 103) 104 ± 34 93 ± 33 81 ± 43 54 ± 25* 0.009
ISR AUC0–300 (pmol/min × min × 103) 233 ± 84 228 ± 98 223 ± 105 207 ± 66 0.551
ISR AUC0–30/glucose AUC0–30 [(pmol × min)/(mmol/L × min)] 45.5 ± 13.8 43.7 ± 12.6 43.7 ± 26.1 52.1 ± 25.0* 0.058
ICR AUC 0–30/insulin AUC0–30 [(L/min × min)/(pmol/L × min ×103)] 11 ± 6 13 ± 4 28 ± 23 37 ± 27 0.048
ICR AUC0–300 (L/min × min) 2.1 ± 0.5 2.2 ± 0.6* 2.6 ± 0.9 3.3 ± 1.0* 0.041
Endogenous glucose production rate AUC0–300 (mmol/min × min) 113 ± 42 103 ± 20 125 ± 42 84 ± 49* 0.108
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Data are means ± SD. Analysis of covariance (ANCOVA) was used to determine the significance of differences between groups after the intervention, adjusted for the Before intervention value.

*

Value significantly different from corresponding Before value by Student’s t-tests for paired samples, P < 0.05. Abbreviations: AUC0–30, area under the curve over the first 30 min of the oral glucose tolerance test; AUC0–300, area under the curve over the entire 300 min oral glucose tolerance test, ISR, insulin secretion rate; ICR, insulin clearance rate.

Figure 1. Plasma glucose and insulin concentrations and glucose and insulin kinetics during the 5-hour oral glucose tolerance test (OGTT).

Figure 1.

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(A–G) Plasma glucose (A) and insulin (B) concentrations, insulin secretion rate (C), insulin secretion rate in relation to plasma glucose concentration during the first 30 min of the OGTT (D), insulin clearance rate (E), insulin clearance rate in relation to plasma insulin concentrations during the first 30 min of the OGTT (F), and endogenous glucose production rate (G) before (white circles) and after (black circles) intervention in the standard care group (n=8) and the intensive lifestyle therapy group (n=10). Abbreviation: EGP, endogenous glucose production. Data are means ± SEM.

β-cell function, insulin kinetics and multi-organ insulin sensitivity

The ISR in relation to plasma glucose concentration during the first 30 min after glucose ingestion, which provides an index of β-cell function when plasma glucose is rapidly increasing, did not change in the SC group but increased in the ILT group (P = 0.058 ILT vs SC; P <0.05 after vs before in ILT group) (Table 2 and Figure 1D). However, total ISR during the 5-hour OGTT (ISR AUC0–300) was not different after than before ILT, even though β-cell function (glucose-stimulated insulin secretion) improved, because plasma glucose was lower after than before the intervention (Table 2 and Figures 1A and 1C). The ICR in relation to plasma insulin concentration during the first 30 min after glucose ingestion was greater after than before ILT, but did not change after SC (P < 0.05, ILT vs SC) (Table 2 and Figure 1F), and total insulin clearance rate during the 5-hour OGTT increased in the ILT group after the intervention, but not the SC group (P < 0.05, ILT vs SC) (Table 2 and Figure 1E). Indices of hepatic, adipose tissue and whole-body insulin sensitivity were assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose and palmitate tracer infusions. The hepatic insulin sensitivity index (reciprocal of the product of basal endogenous glucose production rate and basal plasma insulin concentration) increased by ~150%, the adipose tissue insulin sensitivity index (reciprocal of the product of basal palmitate rate of appearance [Ra] and basal plasma insulin concentration) increased by ~140%, and whole-body insulin sensitivity (defined as glucose disposal rate [Rd] per kg FFM divided by plasma insulin during the hyperinsulinemic-euglycemic clamp procedure, which provides a reliable index of skeletal muscle glucose uptake (Koh et al., 2021)) increased by ~110% in the ILT group, but none of these outcomes changed in the SC group (all P ≤ 0.001, ILT vs SC) (Figure 2).

Figure 2. Multi-organ insulin sensitivity.

Figure 2.

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(A–C) Hepatic insulin sensitivity index (A), adipose tissue insulin sensitivity index (B), and whole-body insulin sensitivity (C) before (white bars) and after (gray bars) the intervention in the standard care (SC) (n=8) and intensive lifestyle therapy (ILT) (n=10) groups. Values are means ± SEM and circles represent individual participant values. *Value significantly different from corresponding value in the SC group by using ANCOVA after adjusting for the Before intervention value, P < 0.01. Abbreviations: glucose Ra, rate of glucose appearance into the bloodstream (expressed as μmol/kg fat-free mass [FFM] per minute); palmitate Ra, rate of palmitate appearance into the bloodstream (expressed as μmol/kg FFM per minute); glucose Rd, glucose disposal rate (expressed as μmol/kg FFM per minute during the hyperinsulinemic-euglycemic clamp procedure).

Skeletal muscle gene expression and metabolite content

There were 65 differentially expressed genes (DEGs, log2 |fold change| >0.3 and False Discovery Rate <0.05) in the SC group and 1,540 DEGs in the ILT group after compared with before the intervention (Figure 3A and Tables S2 and S3). Ingenuity Pathway Analysis was used to identify the biological pathways that were significantly (P<0.05) enriched with the DEGs in the ILT group. The top 10 pathways that were highly enriched in DEGs included pathways involving mitochondrial biogenesis and function (Mitochondrial Dysfunction, Oxidative Phosphorylation, and Tricarboxylic Acid [TCA] Cycle II, Sirtuin Signaling Pathway, NAD Signaling Pathway) (Figure 3B). Consistent with these pathway analyses, ILT significantly increased skeletal muscle gene expression of: i) nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme; ii) mitochondrial sirtuin (SIRT3) and PPARgamma Coactivator 1 Alpha (PPARGC1A), which are downstream targets of NAD signaling and master regulators of mitochondrial biogenesis and function; iii) mitochondria-encoded proteins (e.g., MT-ND1, MT-ND5); and iv) proteins involved in regulating mitochondrial oxidative metabolism (e.g., SOD2, COX4l1, CS, CYCS) and angiogenesis (VEGFA) (Figure 3C). Based on these findings we evaluated whether muscle metabolites in the ILT group support the muscle transcriptomics data and found evidence of increased NAD+ metabolism (increased NAD+) and TCA cycle activity (increased citrate, aconitate, fumarate, and malate) (Figure 3D). Together, these results suggest ILT enhances skeletal muscle mitochondrial metabolism through activation of the NAMPT-mediated NAD+ biosynthesis-SIRT3-PPARGC1A axis (Figure 3E).

Figure 3. Skeletal muscle gene expression and mitochondrial metabolites.

Figure 3.

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(A–D) Skeletal muscle tissue obtained before and after the intervention in the Standard Care (SC) (n=6) and Intensive Lifestyle Therapy (ILT) (n=8) groups were evaluated by using RNA-sequencing (RNA-seq). (A) Volcano plots of skeletal muscle RNA-seq data with log2-fold change (FC) (X-axis) and -log10-P value (Y-axis). The number of differentially expressed genes (DEGs, log2 |FC | >0.3 and False Discovery Rate <0.05) between before and after the intervention is shown in a box. (B) Ingenuity Pathway Analysis (IPA) was used to identify the biological pathways that were significantly (P<0.05) enriched with the DEGs in the ILT group. The top 10 pathways that were highly enriched in DEGs are shown. (C) Skeletal muscle gene expression of DEGs involved in NAD+ and sirtuin signaling and mitochondrial biogenesis and function before (white bars) and after (gray bars) the intervention. (D) Skeletal muscle NAD+ content and the content of tricarboxylic acid cycle intermediates in the ILT group (n=8) before (white bars) and after (gray bars) the intervention. (E) A schematic overview of the proposed mechanisms explaining the metabolic benefit induced by ILT. Values are means ± SEM and circles represent individual participant values. Px denotes the statistical significance of the effects of ILT compared with SC by using ANCOVA. P denotes the statistical significance of differences in values before and after ILT by using the Student’s t-tests for paired samples.

Adipose tissue gene expression

The expression of genes involved in adipose tissue extracellular matrix (ECM) remodeling (SPARC, LOX, LOXL1, TNMD, PDGFA, SEMA3C) were downregulated after ILT but did not change after SC (Figure 4A). The expression of genes related to adipose tissue inflammation (IL6, TNF, CCL2, CCL5, CD68, CD74) did not change in either the SC or ILT groups (Figure 4B).

Figure 4. Adipose tissue gene expression.

Figure 4.

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(A–B) The expression of adipose tissue genes involved in (A) extracellular matrix remodeling (SPARC, LOX, LOXL1, TNMD, PDGFA, SEMA3C) and (B) inflammation (IL6, TNF, CCL2, CCL5, CD68, CD74) before (white bars) and after (gray bars) the intervention in the Standard Care (SC) (n=7) and Intensive Lifestyle Therapy (ILT) (n=10) groups. Values are means ± SEM and circles represent individual participant values. Px denotes the statistical significance of the effects of ILT compared with SC by using ANCOVA. P denotes the statistical significance of differences in values before and after ILT by using the Student’s t-tests for paired samples.

DISCUSSION

Diet-induced weight loss and increased physical activity are considered the cornerstone of therapy for people with obesity and T2D (American Diabetes Association, 2020). However, providing an effective lifestyle intervention is often difficult because of lack of provider expertise or programs, patient inconvenience, cost, and non-adherence. The results from the present study demonstrate that intensive lifestyle therapy delivered at the worksite: i) causes marked weight loss and beneficial changes in body composition (decreased body fat mass, intra-abdominal adipose tissue volume, and intrahepatic triglyceride content without a decrease in FFM or appendicular lean mass); ii) increases cardiorespiratory fitness and muscle strength; iii) improves glycemic control (decreased fasting and postprandial plasma glucose, HbA1c, and use of diabetes medications) and can induce diabetes remission; iv) improves the major physiological factors involved in the pathogenesis of T2D, namely β-cell function and multi-organ insulin sensitivity; and v) causes beneficial cellular changes in skeletal muscle and adipose tissue biology; and vi) reduces circulating PAI-1, which is likely a mediator of systemic insulin resistance. We conclude that marked weight loss and increased physical activity can be achieved through intensive lifestyle therapy at the worksite, which has profound therapeutic clinical, physiological and cellular effects in people with obesity and T2D. Therefore, an intensive calorie-reduced diet and exercise intervention should be considered a primary therapy from “Day 1” to treat and reverse T2D. Moreover, our data demonstrate that an effective intensive lifestyle program can be implemented at the worksite, which has important implications for national dissemination in the management of people with obesity and T2D.

Multi-organ insulin resistance is the most common metabolic complication of obesity and is involved in the pathogenesis of dyslipidemia, nonalcoholic fatty liver disease and T2D (Klein et al., 2022). Weight loss in people with obesity improves multi-organ insulin sensitivity; even moderate (i.e., 5%) weight loss improves insulin action in the liver, adipose tissue and skeletal muscle, and progressive amounts of weight loss cause corresponding progressive increases in multi-organ insulin sensitivity (Magkos et al., 2016). Weight loss typically improves hepatic insulin sensitivity before skeletal muscle insulin sensitivity in people with T2D, which contributes to the early improvements in glycemic control (Lim et al., 2011; Petersen et al., 2005; Steven et al., 2016). Regular exercise, independent of weight loss, also has beneficial effects on hepatic, adipose tissue, and skeletal muscle insulin sensitivity (Coker et al., 2009; Polak et al., 2005; Riis et al., 2019), and the combination of endurance and resistance exercise has greater therapeutic effects than either alone on glycemic control in people with T2D (Church et al., 2010; Sigal et al., 2007). In the present study, we attempted to maximize the effects of lifestyle therapy on multi-organ insulin sensitivity by combining marked diet-induced weight loss with both endurance and resistance exercise training, which increased hepatic, adipose tissue and whole-body insulin sensitivity by 100–150%. Our data suggest alterations in skeletal muscle and adipose tissue biology and a decrease in circulating PAI-1 are likely involved in mediating the marked improvement in insulin action. In skeletal muscle, the expression of genes and the content of metabolites related to mitochondrial function and NAD-sirtuin signaling markedly increased after ILT.

These changes included an increase in muscle NAMPT, SIRT3 and PPARGC1A expression and muscle content of NAD+ and TCA cycle intermediates, suggesting ILT increases muscle NAMPT-mediated NAD+ biosynthesis, which stimulates mitochondrial sirtuin signaling pathways that in turn activate PPARGC1A, a master regulator of mitochondrial biogenesis and function. Decreased skeletal muscle mitochondria content, impaired mitochondrial function, and decreased SIRT3 are associated with T2D, and impair insulin signaling by increasing the production of reactive oxygen species and causing oxidative stress (Jing et al., 2011; Lantier et al., 2015; Szendroedi et al., 2011). Therefore, it is possible that the exercise-induced increase in capacity for oxidative phosphorylation improved insulin resistance in our ILT group by decreasing oxidative stress (Hesselink et al., 2016; Karolkiewicz et al., 2009). The importance of NAD+ and SIRT3 in skeletal muscle metabolic function has been demonstrated in studies conducted in rodent models that found both enhancing NAD+ biosynthesis by administering nicotinamide mononucleotide (NMN) and overexpressing SIRT3 increase muscle mitochondrial function and insulin action (Jing et al., 2011; Lantier et al., 2015). In adipose tissue, ILT caused a downregulation in the expression of genes involved in ECM remodeling, which is associated with increased systemic insulin sensitivity in both rodents and humans (Beals et al., 2021; Sun et al., 2013). The potential importance of decreased ECM remodeling in regulating whole-body insulin action is further supported by studies that found progressive weight loss in people with obesity causes a progressive increase in insulin sensitivity in conjunction with a progressive decrease in the expression of ECM genes (Magkos et al., 2016) and adipose tissue collagen VI knock-out in mice prevents obesity-induced insulin resistance (Khan et al., 2009). There were no changes in the adipose tissue expression of a series of genes involved in inflammation in either the SC or ILT groups, suggesting these general markers of adipose inflammation were not involved in the improvement in ILT-induced insulin sensitivity. Finally, we found ILT caused a marked decrease in plasma PAI-1 concentration, which is a potentially important mediator of systemic insulin resistance. In rodents, adipocyte-specific PAI-1 overexpression causes insulin resistance whereas whole-body and adipocyte-specific knockouts of PAI-1 improve insulin action (Alessi et al., 2007). In addition, we have previously found that plasma PAI-1 24-h AUC was inversely associated with hepatic and skeletal muscle insulin sensitivity (Fuchs et al., 2021). Together, these findings suggest a complex interaction among multiple organs contribute to the improvement in insulin sensitivity induced by weight loss and exercise.

Beta-cell function is impaired in people with T2D because of decreases in both β-cell mass and β-cell sensitivity to glucose (Meier et al., 2012; Nichols et al., 2020). Beta-cell function, assessed in the present study as the rate of insulin secretion in response to a rise in plasma glucose concentration during the first 30 min after glucose ingestion, increased after ILT with no change in the SC group. In addition to the improvement in this “early phase” of insulin secretion, ILT increased glucose-stimulated insulin secretion during the entire 5-h postprandial period after glucose ingestion. Therefore, the ISR during the OGTT after ILT was not different than the values before ILT, even though plasma glucose was lower after the intervention. The mechanism responsible for the beneficial effect of ILT on β-cell function is not known and could have included an increase in pancreatic β-cell mass, or an increase in β-cell sensitivity to glucose, or both. It has been proposed that, in people with T2D, high plasma glucose and triglyceride concentrations act synergistically to induce β-cell dysfunction and death, mediated by oxidative, mitochondrial, and endoplasmic reticulum stress, and β-cell dedifferentiation (Weir, 2020). Therefore, the large decrease in plasma glucose and triglyceride concentrations after ILT could have contributed to the improvement in β-cell function. It has also been proposed that a decrease in intrapancreatic fat content, which occurs with weight loss in people with T2D, contributes to the recovery of β-cell function by decreasing local triglyceride lipolysis and both interstitial and intracellular fatty acid concentrations (Steven et al., 2016; Taylor et al., 2018).

Plasma insulin concentration is determined by the balance between insulin secretion by β-cells and plasma insulin clearance by the liver, kidneys and skeletal muscle (Koh et al., 2022). Insulin clearance is a saturable receptor-mediated process, and insulin receptors are internalized and removed from the cell surface after insulin binding (Mondon et al., 1975; Najjar and Perdomo, 2019), which helps explain the rapid decline in ICR in our participants after glucose ingestion when the ISR and plasma insulin concentrations were rapidly increasing. Our data demonstrate that ILT causes a decrease in postprandial plasma insulin concentrations, primarily because of an increase in ICR, rather than a decrease in β-cell glucose-stimulated insulin secretion. Moreover, the increase in ICR was not simply due to a decrease in circulating insulin, because insulin clearance was greater after than before ILT at any given plasma insulin concentration. The mechanism responsible for the increase in clearance is likely due to both weight loss- and exercise-induced effects on insulin sensitivity, presumably related to decreased plasma insulin concentrations and increased insulin cell surface receptors; basal ICR is directly related to insulin sensitivity and ICR after glucose ingestion is inversely associated with plasma insulin concentration (Mittendorfer et al., 2022). In addition, exercise training, itself, without weight loss, increases both liver (Hari et al., 2020; Wirth et al., 1982) and skeletal muscle (Frosig et al., 2007) insulin extraction.

Type 2 diabetes is associated with decreased cardiorespiratory fitness and muscle strength, which are associated with increased mortality and decreased physical function (Carnethon et al., 2009; Kalyani et al., 2015; Kim et al., 2018; Park et al., 2006; Ruiz et al., 2008; Tarp et al., 2019). Supervised exercise training as part of the ILT caused about a 25% improvement in both cardiorespiratory fitness (peak oxygen consumption) and muscle strength (total 1RM [sum of the maximum weight lifted during leg press, bench press, seated row, and knee flexion exercises]). The improvement in muscle strength in the ILT group occurred without any change in fat-free mass and appendicular lean mass, and was likely caused by neuromuscular adaptations in combination with alterations in skeletal muscle architecture, which improve force transduction (Folland and Williams, 2007). Exercise training-induced improvement in cardiorespiratory fitness is largely attributed to increased maximal stroke volume and red blood cell expansion, which together increase oxygen delivery to working muscles in concert with a smaller contribution from greater muscle capillarization, mitochondrial density and oxidative capacity combining to improve oxygen extraction and utilization (Lundby et al., 2017).

The ILT intervention was delivered at the worksite to aid compliance with weekly dietary counselling sessions and supervised exercise training 4 days/week. There has been a rapid growth of employer-provided wellness programs aimed at improving the health and productivity of employees and reducing overall healthcare costs, and about 84% of large companies in the United States provided a health and wellness program in 2019 (Kaiser Family Foundation, 2019). However, the success of these programs, measured by the extent of weight loss, has typically been modest with minimal reductions in body mass (i.e., <5%) observed in most studies (Almeida et al., 2015; Benedict and Arterburn, 2008; Kramer et al., 2015; Shrestha et al., 2018). In contrast, participants randomized to the ILT group in the present study lost, on average, 17% of their initial body weight, which led to marked improvements in body composition, metabolic function and glycemic control. The reasons for the greater success in the present study than previous studies are likely: i) frequent face-to-face contact between the ILT intervention team and participants; ii) the supervised nature of all components of the intervention; iii) group exercise sessions; and iv) convenient access at a worksite that facilitated high attendance rates for the weekly dietary and behavioral (98%) and supervised exercise training (92%) sessions. Clinically important decreases in body weight and improvements in glycemic control were also reported in the DiRECT study, which was conducted in primary care practices in the United Kingdom where the intervention was implemented by nurse and dietitian teams (Lean et al., 2018). The worksite-intervention reported in the present study provides a template for an effective lifestyle treatment program outside of a clinical practice. Future research is warranted to optimize implementation and dissemination of similar ILT programs across a variety of workplaces and populations, including employee subgroups less likely to participate in clinic-based weight loss programs (e.g., minority and low-socioeconomic status employees).

The present study demonstrates the profound effects of calorie restriction and multi-modal exercise training on glycemic control (fasting and postprandial plasma glucose, HbA1c, and need for diabetes medications), the physiological factors involved in the pathogenesis of T2D (β-cell function and multi-organ insulin sensitivity), and several putative cellular (skeletal muscle mitochondrial function and adipose tissue ECM formation) and systemic (circulating PAI-1) factors involved in mediating these beneficial outcomes. In addition, ILT increases cardiorespiratory fitness and muscle strength, which have a positive effect on physical function. These results underscore the importance of aggressive ILT in the management of T2D, which is typically not successfully implemented, and demonstrate the potential dissemination of accessible ILT at the worksite.

Limitations of the study

Our study was a hypothesis-testing pathophysiology study. Therefore, ILT was provided by research personnel with experience in weight management and exercise therapy, which could affect the ability of other worksites to obtain similar weight loss efficacy and improvements in cardiometabolic outcomes. However, the diet intervention followed a specific format that can easily be delivered by a dietitian with minimal additional training, and the exercise intervention followed a standardized template for all recipients. In addition, our study identified associations between the improvements in metabolic and physical function and cellular changes in skeletal muscle and adipose tissue biology, but cannot determine true causal relationships, which is a common limitation in human studies for obvious reasons. However, these associations identify potential mechanisms that can be targeted in studies conducted in animal models that are able to evaluate the effect of manipulating these specific metabolic pathways on metabolic outcomes.

STAR METHODS

Resource Availability

Lead Contact

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Samuel Klein (sklein@wustl.edu).

Materials Availability

This study did not generate new unique reagents.

Data and Code Availability

  • RNA-seq data have been deposited in the NCBI GEO database and the accession number is listed in the key resources table. Raw data used to generate the descriptive statistics presented in this manuscript are provided in Data S1.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

KEY RESOURCES TABLE

REAGENT or RESOURCE SOURCE IDENTIFIER
Chemicals, Peptides, and Recombinant Proteins
[6,6-2H2]glucose Cambridge Isotope Laboratories Cat# DLM-349-MPT-PK
[U-13C]glucose Cambridge Isotope Laboratories Cat# CLM-1396-MPT-PK
[U-13C]palmitate Cambridge Isotope Laboratories Cat# CLM-3943-MPT-PK
Regular insulin (human recombinant) Lily USA Humulin R U100
Dextrose 20% IV solution Hospira Cat# 793519
75-g glucose solution ThermoFisher SCIENTIFIC Cat# TGP401223PA
Acetonitrile for LC/MS Fisher chemical Cat# A955–4; CAS# 75–05-8
Methanol for LC/MS Fisher chemical Cat# A456–4; CAS# 67–56-1
Water for LC/MS Fisher chemical Cat# W6–4; CAS# 7732–18-5
2-propanol for LC/MS Fisher chemical Cat# A461–4; CAS# 67–63-0
Medronic acid MilliporeSigma Cat# 64255; CAS# 1984–15-2
Ammonium bicarbonate MilliporeSigma Cat# 5.33005; CAS# 1066–33-7
Ammonium hydroxide Fluka Cat# 44273; CAS# 1336–21-6
Formic acid Fisher chemical Cat# A117–50; CAS# 64–18-6
Ammonium formate MilliporeSigma Cat# 70221; CAS# 540–69-2
Critical Commercial Assays
Glucose concentration Yellow Springs Instruments YSI 2300 Stat Plus
Insulin and C-peptide concentrations Roche Elecsys 2010 immunoassays
Triglyceride concentration Roche Cat# 20767107322
High density lipoprotein concentration Roche Cat# 07528566190
HbA1c – Hemolyzing agent Roche Cat# 04528182190
HbA1c - Assay Roche Cat# 05336163190
Adiponectin concentration MilliporeSigma Cat# HADP-61HK
PAI-1 concentration MilliporeSigma Cat# HNDG3MAG-36K
Deposited data
Skeletal muscle RNA-sequencing data NCBI GEO database Accession# GSE205891
Software and Algorithms
Excel Microsoft N/A
SPSS version 27 IBM N/A
R R-Project N/A
edgeR R Bioconductor Bioconductor N/A
Ingenuity Pathway Analysis Qiagen N/A
EndNote Version X9.3.3 Clarivate Analytics N/A
Skyline University of Washington https://skyline.ms
Qualitative Analysis 10.0 Agilent Technologies N/A
Other
TRIzol Reagent Invitrogen Cat# 15596018
RNeasy mini kit Qiagen Cat# 74106
RNase-free DNase Set Qiagen Cat# 79254
iHILIC®-(P) Classic, Guard Column HILICON Cat# 160.122.0520
iHILIC®-(P) Classic, HILIC Column HILICON Cat# 160.102.0520
Acquity UPLC® HSS T3 VanGuard Pre-Column Waters Cat# 186003540
Acquity UPLC® HSS T3 Column Waters Cat# 186003976
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Experimental Model and Subject Details

This randomized, controlled trial was conducted in people with obesity and T2D who were employees at Washington University or BJC HealthCare in St. Louis, MO, which is affiliated with Washington University. After completing baseline assessments of body composition, cardiorespiratory fitness, muscle strength, and metabolic function, participants were randomly assigned to either the standard care (SC) group or the intensive lifestyle therapy (ILT) group. All baseline testing was repeated after ~7–8 months in both groups. Post-intervention testing in the ILT group was conducted the day after an exercise training session and after participants were weight stable for ~3 weeks. Testing was conducted in the Clinical and Translational Research Unit and the Center for Clinical Imaging Research at Washington University School of Medicine in St. Louis, MO. All participants provided written informed consent before participating in this study, which was approved by the Institutional Review Board of Washington University School of Medicine in St. Louis, MO.

Twenty-three men and women with obesity and T2D enrolled in this study. All participants completed a comprehensive screening evaluation consisting of a medical history and physical examination, standard blood tests, and a resting electrocardiogram. In addition, exercise stress echocardiography was performed to exclude participants with contraindications for participation in a rigorous exercise program. Potential participants were excluded if they: 1) were being treated with >0.5 units of insulin/kg body weight per day; 2) had any change in diabetes medication in the previous 3 months; 3) had serious cardiovascular disease, including acute coronary syndrome, heart failure requiring medications, or class III or IV heart failure according to the New York Heart Association criteria; 4) had uncontrolled proliferative diabetic retinopathy or severe peripheral neuropathy; 5) exercised regularly (>60 min of structured exercise per week); 6) used tobacco products regularly; or 7) used any medications, other than diabetes medications, that could affect the study outcome measures.

Twelve participants (11 women and 1 man) were randomized to the SC group and 11 participants (10 women and 1 man) to the ILT group. Four participants in the SC group withdrew from the study because they either lost interest in participating, moved from the St. Louis area or had a new diagnosis of an exclusionary medical condition, and one participant in the ILT group was removed from the study because she did not complete the study testing procedures. Accordingly, 8 participants in the SC group (all women) and 10 participants in the ILT group (9 women and 1 man) completed the study and their data were included in the final data analysis (Figure S1).

Method Details

Body composition, cardiorespiratory fitness and muscle strength testing

Total body fat mass, fat-free mass (FFM) and appendicular lean mass were determined by using dual-energy X-ray absorptiometry (Lunar iDXA, GE Healthcare Lunar). Intra-abdominal adipose tissue volume was determined by using magnetic resonance imaging, and intrahepatic triglyceride content was determined by using magnetic resonance spectroscopy (3T superconducting magnet, Siemens, Iselin, NJ). One participant in the SC group did not undergo magnetic resonance imaging because of claustrophobia. Cardiorespiratory fitness, defined as peak oxygen consumption (VO2peak), was determined by using continuous indirect calorimetry (Parvo Medics TrueOne 2400, Sandy, UT) during a progressive cycle ergometer (Lode Excalibur sport, Groningen, the Netherlands) test to volitional exhaustion (Pellikka et al., 2007). Muscle strength was assessed as the sum of the maximal weights lifted during one-repetition maximum (1-RM) tests of four different exercises (leg press, knee flexion, seated row, and chest press) by using a Hoist multi-station weight machine (Hoist Fitness Systems, Poway, CA) (Smith et al., 2015). Total 1-RM data were not included for two participants; one SC participant because they did not complete the chest press 1-RM assessments and one ILT participant, because they lifted the maximum weight possible on the Hoist weight machine at baseline so the 1-RM assessment was not repeated after ILT.

Metabolic testing: 5-hour oral glucose tolerance test, hyperinsulinemic-euglycemic clamp procedure, and muscle and adipose tissue biopsies

Participants stopped their diabetes medications before metabolic testing to reduce their effect on the study outcomes; glucagon-like-peptide-1 receptor agonists were discontinued two weeks, other oral diabetes medications three days, and insulin one day before each metabolic study. On the day before testing, participants were admitted to the Clinical and Translational Research Unit in the late afternoon and consumed a standard evening meal that contained 50% of calories as carbohydrate, 30% as fat, and 20% as protein. The following morning, after participants fasted overnight, a catheter was inserted into a forearm vein to infuse insulin, dextrose and stable isotopically labeled glucose and palmitate tracers, and a second catheter was inserted into a radial artery for blood sampling. At 0500 h, a blood sample was collected to determine baseline plasma glucose and palmitate enrichments, and a primed (32 μmol/kg body weight), continuous (0.32 μmol/kg body weight/min) infusion of [6,6-2H2]glucose (Cambridge Isotope Laboratories, Cambridge, MA) was started and maintained for 8.5 h to evaluate glucose kinetics. At 0700 h, a 90-min infusion of [U-13C]palmitate (Cambridge Isotope Laboratories) (6 nmol/kg FFM/min) was started to assess basal fatty acid kinetics Blood samples were obtained every 10 min (3 samples) between 0810 h and 0830 h (190 to 210 min after starting the glucose tracer infusion) to determine basal plasma glucose, insulin and C-peptide concentrations, and glucose and palmitate kinetics. Immediately afterwards (at 0830 h), participants ingested a 75-g glucose solution (NERL™ Trutol™ Glucose Tolerance Test Beverages, ThermoFisher SCIENTIFIC) mixed with 1.5 g [U-13C]glucose (Cambridge Isotope Laboratories). Blood samples were collected every 10 min for the first 30 min, every 15 min for the next 30 min, and then every 20 min for the next 4 hours to determine plasma glucose, insulin and C-peptide concentrations and glucose kinetics. At 1330 h, a hyperinsulinemic-euglycemic clamp procedure was started and continued for 3.5 h; insulin was infused at 50 mU/m2 body surface area/min (initiated with an insulin infusion of 200 mU/m2 body surface area/min for 5 min and then 100 mU/m2 body surface area/min for 5 min). Plasma glucose concentration was maintained at ~100 mg/dL during insulin infusion by variable rate infusion of 20% dextrose enriched to 2.5% with [6,6-2H2]glucose and the infusion of [6,6-2H2]glucose was stopped. Blood samples were collected every 10 min during the final 20 min (3 samples) of the clamp procedure to determine plasma glucose and insulin concentrations, and glucose kinetics.

At ~0630 h, during the basal period of the metabolic study, muscle tissue was obtained from the vastus lateralis by percutaneous biopsy by using a Tilley-Henkel forceps (Sontec Instruments, Inc., Centennial, CO) and subcutaneous abdominal adipose tissue was obtained from the periumbilical area by aspiration through a 3-mm liposuction cannula (Tulip Medical Products, San Diego, CA) connected to a 30 cc syringe (Magkos et al., 2016). All samples were immediately rinsed in ice-cold saline and frozen in liquid nitrogen before being stored at −80°C until final analyses.

Standard Care and Intensive Lifestyle Therapy

After completing baseline testing, participants in the SC group received dietary and physical activity instructions as recommended by the American Diabetes Association (ADA) guidelines (American Diabetes Association, 2020), followed by meetings approximately every month for about 7 months with a study team member to record body weight, review diet and physical activity behaviors, and document medication use. During this time, participants continued their routine medical management, including regular clinic visits with their personal physician and/or diabetes educator. Participants randomized to the ILT group participated in a weekly dietary and behavioral education session in addition to four 60-min supervised exercise training sessions per week for 8 months; all dietary-behavioral education and exercise training sessions were conducted at the worksite. Initially, participants were instructed to consume ~500 kcal/day less than their calculated estimated total daily energy requirements (Mifflin et al., 1990), and energy intake was then adjusted weekly as needed to achieve a 0.5%−1.0% weight loss/week and >10% body weight loss within about 28 weeks. Participants were given prepackaged breakfast meals (430 kcal, containing 45 g of carbohydrate, 15 g of fat, and 30 g of protein) that were produced by our metabolic kitchen and could be consumed once daily if desired, and provided guidance for consumption of total daily energy, meal and snack intake. The supervised exercise program included both endurance and resistance exercise training sessions (exercise equipment kindly provided by True Fitness, St. Louis, MO). The intensity of the endurance exercise sessions was progressively increased to attain a heart rate equivalent to 70% to 80% of VO2peak during the entire training period. Resistance exercise training was performed by using a Hoist multi-station weight machine (Hoist Fitness Systems, Poway, CA) and targeted all major muscle groups. For each exercise, 2–3 sets of 6–8 repetitions/set were performed at 80% of 1RM. The intensity of the exercise was increased about every 2 weeks based on repeated evaluations of 1RM. During the final 3 weeks of the ILT intervention, dietary energy intake was adjusted to maintain a stable body weight (±2%) until the testing procedures performed at baseline were repeated. Blood glucose concentration values were reviewed weekly by telephone or in person in the SC group and in person in the ILT group. The doses of diabetes medications were adjusted every 1–2 weeks in the ILT group, as needed to avoid hypoglycemia; any medications changes in the SC group were made by the participants’ personal physicians.

Sample analyses

Blood samples.

Plasma glucose concentration was determined by using an automated glucose analyzer (YSI 2300 STAT plus; Yellow Spring Instrument Co, Yellow Springs, OH). Plasma insulin and C-peptide concentrations were determined by using electrochemiluminescence technology (Elecsys 2010, Roche Diagnostics). Plasma adiponectin, PAI-1, triglyceride, and HDL-cholesterol concentrations and hemoglobin A1c (HbA1c) were measured in the Washington University Clinical Core Laboratory. Plasma glucose and palmitate tracer-to-tracee ratios (TTRs) were determined by using gas chromatography/mass spectrometry (GC-MS) as described previously (Magkos et al., 2016).

Skeletal muscle and adipose tissue RNA-sequencing.

Total RNA was isolated from frozen skeletal muscle and subcutaneous adipose tissue samples by using TRIzol Reagent (#15596018; Invitrogen) and RNeasy mini kit (Qiagen, Valencia, CA), respectively, in combination with an RNase-free DNase Set (Qiagen) (Yoshino et al., 2021). Library preparation of the samples was performed with total RNA and cDNA fragments sequenced on an Illumina NovaSeq 6000 (Illumina, San Diego, CA).

Skeletal muscle mitochondrial metabolites.

Based on the data obtained from the muscle transcriptomics, we analyzed muscle metabolites related to mitochondrial function and substrate oxidation in the ILT group. Metabolites were extracted from frozen tissue samples by using an Omni Bead Ruptor Eluite Homogenizer and acetonitrile:methanol:water (2:2:1, x 40 μL/mg tissue). Metabolite extracts were evaluated by using an Agilent 1290 Infinity II liquid chromatography (LC) system (Agilent Technologies, Santa Clara, CA) coupled to an Agilent 6545 QTOF mass spectrometer. To separate polar metabolites, sample extracts were analyzed with an iHILIC®-(P) Classic column (2.1 mm x 100 mm, 5 μm, with a guard column) at 45°C and a flow rate of 250 μL/min as previously described(Yoshino et al., 2021). To separate nonpolar metabolites, the same sample extracts were also analyzed with an Acquity UPLC® HSS T3 column (2.1 × 150 mm, 1.8 μm, with a pre-column) at 60°C and a flow rate of 250 μL/min as previously described(Sindelar et al., 2021). To separate nonpolar metabolites, the same sample extracts were also analyzed with an Acquity UPLC® HSS T3 column (2.1 × 150 mm, 1.8 μm, with a pre-column) at 60°C and a flow rate of 250 μL/min as previously described (Sindelar et al., 2021).

Calculations

Diabetes medication score.

A composite diabetes medication score for each participant was calculated based on the number and doses of diabetes medications prescribed, as described previously (Klein et al., 2012). For each medication, with the exception of insulin, a numerical score was calculated as the daily prescribed dose relative to the maximum recommended dose. For insulin, a numerical score was calculated as the daily dose relative to a standard dose of 1 IU of insulin per kg of body weight per day.

Metabolic response to glucose ingestion.

Areas under the curve (AUCs) for plasma glucose and insulin concentrations, and insulin secretion rate (ISR) and insulin clearance rate (ICR) were calculated over the first 30 min (AUC0–30) and entire 5-h (AUC0–300) after glucose ingestion by using the trapezoid method. The ISR was determined by fitting the basal and postprandial plasma C-peptide concentrations to a two-compartment model by using a time-variable ISR function in conjunction with population-based C-peptide kinetic parameters (Van Cauter et al., 1992; van Vliet et al., 2020). The plasma ICR was calculated as the volume of plasma that is cleared of insulin per min. During steady-state basal conditions, the rate of insulin removal equals the rate of insulin secretion, so ICR was calculated as ISR (in pmol/min) divided by the plasma insulin concentration (in pmol/L). After glucose ingestion, the ICR over a given time interval was calculated as the integral of the ISR (adjusted for increases or decreases in plasma insulin pool size over the time interval) divided by the mean insulin concentration over the time interval (Gastaldelli et al., 2021), assuming a plasma volume of 55 mL/kg FFM (Boer, 1984). Endogenous glucose rate of appearance (Ra) into the systemic circulation Ra (i.e., endogenous glucose production rate) before and after glucose ingestion were calculated as previously described (Bradley et al., 2012).

Insulin sensitivity and β-cell function.

An index of hepatic insulin sensitivity was calculated as the reciprocal of the product of basal endogenous glucose Ra in the systemic circulation and basal plasma insulin concentration [1000/(μmol/kg FFM/min × pmol/L)] (Smith et al., 2020). An index of adipose tissue insulin sensitivity was calculated as the reciprocal of the product of basal palmitate Ra and basal plasma insulin concentrations [1000/(μmol/kg FFM/min × pmol/L)] (Fabbrini et al., 2011). An index of whole-body insulin sensitivity was calculated as glucose disposal rate (Rd) per kg FFM divided by plasma insulin during the hyperinsulinemic-euglycemic clamp procedure (Koh et al., 2021). β-cell function was assessed as the relationship between ISR and plasma glucose concentration during the first 30 min of the OGTT, when plasma glucose concentration rapidly increases (Mittendorfer et al., 2022).

Quantification and Statistical Analysis

Student’s t-test for paired samples was used to assess the statistical significance of differences in values before and after intervention within each group. Analysis of covariance (ANCOVA), with the post-intervention value as the dependent variable and the baseline value as the covariate, was used to evaluate the significance of the effects of ILT compared with SC on study outcomes. Prior to the analyses, outcome variables were tested for normality by using the Shapiro-Wilks test, and non-normally distributed variables were log transformed for inferential statistical analysis and back transformed for presentation. Repeated-measures analysis of variance (ANOVA) was used to evaluate the statistical significance of the effects of ILT compared with SC on skeletal muscle and adipose tissue gene expression of selected proteins. P-value and false discovery rate (FDR) for each gene were calculated by using the edgeR R Bioconductor package. Genes with log2 |fold change| > 0.3 and FDR < 0.05 were considered differentially expressed genes (DEGs). Pathway analyses on DEGs were performed by using Ingenuity Pathway Analysis (IPA) software (QIAGEN). Pathways with a P value <0.05 were considered to be significantly enriched. All data are presented as means ± SD unless otherwise indicated. Statistical significance was set at P<0.05. Statistical analyses were performed by using SPSS Version 27 (IBM SPSS, Chicago, IL).

The primary outcome of the study was the change in whole-body insulin sensitivity. We hypothesized that the change in whole-body insulin sensitivity in the ILT group would be more than 15% greater than the corresponding change in the SC group. Based on the inter-individual variability of insulin-mediated stimulation of glucose Rd assessed by using the hyperinsulinemic-euglycemic clamp procedure in a cohort of participants with obesity and T2D that we previously studied (Klein et al., 2004), we estimated that 10 participants per group would be needed to detect a between-group difference of 12.2 (nmol/kg FFM/min)/(pmol/L), which represents a 15% difference based on an expected mean insulin-mediated glucose disposal rate of 84 nmol/kg FFM/min per pmol/L, at baseline with the assumptions of a two-tailed test, an α-value of 0.05 and a power of 0.8. Therefore, we enrolled 12 participants in the SC group and 11 participants in the ILT group, assuming one to two participants in each group would drop out or be withdrawn before completing all post-intervention testing. The computation was performed by using G*Power 3.1.9.7.

Supplementary Material

1

Data S1. Unprocessed data underlying the display items in the manuscript, related to Tables 1,2 and S1 and Figures 1–4 and S2–S3.

2

Document S1. Figure S1-S3 and Tables S1-S2.

4

Table S3. Complete list of differentially expressed genes (DEGs) in skeletal muscle in the ILT group, Related to Figure 3.

Highlights.

  • Worksite-based intensive lifestyle therapy (ILT) causes marked weight loss

  • ILT markedly improves β-cell function and multi-organ insulin sensitivity

  • Metabolic effects are associated with changes in muscle and adipose tissue biology

ACKNOWLEDGEMENTS

We thank the staff of the Center for Human Nutrition at Washington University School of Medicine and the Clinical and Translational Research Unit for assistance in conducting the metabolic studies and their technical assistance in processing and analyzing the study samples, and the study participants for their participation. This study was supported by NIH grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), and UL1 TR000448 (Washington University Institute of Clinical and Translational Sciences), and grants from the National Dairy Council and the American Egg Board.

Footnotes

ADDITIONAL RESOURCES

Clinical Trial Registration Number NCT01977560 (https://clinicaltrials.gov/ct2/show/NCT01977560)

DECLARATION OF INTERESTS

S.K. serves on scientific advisory boards for Altimmune and Merck, and as a consultant for B2M Medical. The other authors have nothing to disclose.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

Data S1. Unprocessed data underlying the display items in the manuscript, related to Tables 1,2 and S1 and Figures 1–4 and S2–S3.

NIHMS1832259-supplement-1.xlsx (166.4KB, xlsx)
2

Document S1. Figure S1-S3 and Tables S1-S2.

NIHMS1832259-supplement-2.pdf (432.6KB, pdf)
4

Table S3. Complete list of differentially expressed genes (DEGs) in skeletal muscle in the ILT group, Related to Figure 3.

NIHMS1832259-supplement-4.xlsx (63.2KB, xlsx)

Data Availability Statement

  • RNA-seq data have been deposited in the NCBI GEO database and the accession number is listed in the key resources table. Raw data used to generate the descriptive statistics presented in this manuscript are provided in Data S1.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

KEY RESOURCES TABLE

REAGENT or RESOURCE SOURCE IDENTIFIER
Chemicals, Peptides, and Recombinant Proteins
[6,6-2H2]glucose Cambridge Isotope Laboratories Cat# DLM-349-MPT-PK
[U-13C]glucose Cambridge Isotope Laboratories Cat# CLM-1396-MPT-PK
[U-13C]palmitate Cambridge Isotope Laboratories Cat# CLM-3943-MPT-PK
Regular insulin (human recombinant) Lily USA Humulin R U100
Dextrose 20% IV solution Hospira Cat# 793519
75-g glucose solution ThermoFisher SCIENTIFIC Cat# TGP401223PA
Acetonitrile for LC/MS Fisher chemical Cat# A955–4; CAS# 75–05-8
Methanol for LC/MS Fisher chemical Cat# A456–4; CAS# 67–56-1
Water for LC/MS Fisher chemical Cat# W6–4; CAS# 7732–18-5
2-propanol for LC/MS Fisher chemical Cat# A461–4; CAS# 67–63-0
Medronic acid MilliporeSigma Cat# 64255; CAS# 1984–15-2
Ammonium bicarbonate MilliporeSigma Cat# 5.33005; CAS# 1066–33-7
Ammonium hydroxide Fluka Cat# 44273; CAS# 1336–21-6
Formic acid Fisher chemical Cat# A117–50; CAS# 64–18-6
Ammonium formate MilliporeSigma Cat# 70221; CAS# 540–69-2
Critical Commercial Assays
Glucose concentration Yellow Springs Instruments YSI 2300 Stat Plus
Insulin and C-peptide concentrations Roche Elecsys 2010 immunoassays
Triglyceride concentration Roche Cat# 20767107322
High density lipoprotein concentration Roche Cat# 07528566190
HbA1c – Hemolyzing agent Roche Cat# 04528182190
HbA1c - Assay Roche Cat# 05336163190
Adiponectin concentration MilliporeSigma Cat# HADP-61HK
PAI-1 concentration MilliporeSigma Cat# HNDG3MAG-36K
Deposited data
Skeletal muscle RNA-sequencing data NCBI GEO database Accession# GSE205891
Software and Algorithms
Excel Microsoft N/A
SPSS version 27 IBM N/A
R R-Project N/A
edgeR R Bioconductor Bioconductor N/A
Ingenuity Pathway Analysis Qiagen N/A
EndNote Version X9.3.3 Clarivate Analytics N/A
Skyline University of Washington https://skyline.ms
Qualitative Analysis 10.0 Agilent Technologies N/A
Other
TRIzol Reagent Invitrogen Cat# 15596018
RNeasy mini kit Qiagen Cat# 74106
RNase-free DNase Set Qiagen Cat# 79254
iHILIC®-(P) Classic, Guard Column HILICON Cat# 160.122.0520
iHILIC®-(P) Classic, HILIC Column HILICON Cat# 160.102.0520
Acquity UPLC® HSS T3 VanGuard Pre-Column Waters Cat# 186003540
Acquity UPLC® HSS T3 Column Waters Cat# 186003976
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RESOURCES