Diabetes-related disparities among U.S. racial and ethnic minority groups persist, despite decades of research on their causes and interventions in an attempt to reduce them. Research demonstrates a strong relationship between diabetes disparities and social determinants of health, the conditions where people are born, live, work, play, worship, and age. While these upstream factors strongly shape health outcomes, they are largely influenced by policy and community-level interventions with limited influence by clinicians or health systems. By contrast, health-related social needs (HRSN) are downstream consequences of adverse social and structural conditions that directly affect individuals and families. These immediate, actionable needs, such as food, housing, and transportation, can be addressed within health care settings. HRSN disproportionately affect racial and ethnic minority communities, with higher prevalence of diabetes, worse outcomes, and greater acute care use. These observations highlight the importance of addressing HRSN in diabetes care given the potential to improve outcomes and achieve diabetes equity. This narrative review summarizes current evidence on identifying and addressing HRSN in health care settings. Recently, significant progress has been made integrating medical and social care for adults with diabetes and HRSN. Specific examples of these efforts with reporting of diabetes outcomes are reviewed here. However, existing research has not yet demonstrated that HRSN interventions consistently reduce diabetes disparities. Additional infrastructure is needed to scale and sustain interventions, enhancing their feasibility, effectiveness, and long-term impact. We conclude with recommendations for research and practice to optimize social care integration for adults with diabetes and achieve diabetes equity.

Incretin-based pharmacology has revolutionized the medical treatment of type 2 diabetes and obesity. The most effective drug to date is tirzepatide, a dual incretin receptor agonist that engages both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). While the relative contributions of GIPR and GLP-1R actions to the clinical effects of tirzepatide have not been established, the potency of this agent has reignited interest in the clinical potential of GIPR agonism. Here, we discuss incretin biology as it relates to metabolic pharmacology and contextualize the mechanisms by which GIPR activity could contribute to the development of new and effective drugs. We explore current and future applications of GIPR agonists and antagonists, to underscore the potential that this signaling system could add to treatment of type 2 diabetes and obesity.

Hyperglycemia during acute pancreatitis (HDAP) likely reflects both stress hormone responses and pancreatic islet injury, distinguishing it from typical stress-induced hyperglycemia. The aim of this study was to determine the prevalence of HDAP and its prognostic significance for early-onset diabetes following acute pancreatitis (AP). Diabetes Related to Acute Pancreatitis and Its Mechanisms (DREAM) is a prospective multicenter study examining the development of diabetes following AP. This analysis included 395 participants without prior diabetes with an AP episode, focusing on their glucose levels during the event. Two definitions of HDAP were examined: peak glucose >140 mg/dL (HDAP140) and >200 mg/dL (HDAP200). Outpatient glycemic status after recovery (median: 111 days post-AP) was evaluated using fasting glucose, oral glucose tolerance test, and HbA1c. HDAP140 and HDAP200 were present in 37.5% and 7.1% of participants, respectively. Age, race, etiology, and AP severity were significant predictors of HDAP140. Among participants with HDAP140, 14.8% developed early-onset diabetes after AP recovery vs. 1.2% in those without (P = 0.0001). In those with HDAP200, 42.9% developed early-onset diabetes vs. 3.5% in those without (P = 0.0001). The absence of HDAP140 and HDAP200 was associated with negative predictive values of 99% and 97%, respectively, for diabetes. HDAP can be common in individuals without diabetes and is associated with early-onset diabetes following AP. Individuals without HDAP have a low risk of diabetes short term, while those with HDAP200 are at high risk. Monitoring glycemia during AP can identify individuals best suited for early targeted postdischarge care.

Glucagon-based polyagonists improve metabolic dysfunction-associated steatotic liver disease (MASLD), which could result from glucagon-stimulated hepatic lipid oxidation. Nevertheless, people with long-standing type 2 diabetes (T2D) exhibit a paradoxical rise in both hepatic lipid content (HLC) and glucagon levels, which has been related to disturbed hepatic metabolism generating glucagonotropic metabolites such as amino acids and nonesterified fatty acids (NEFAs). We examined these relationships in individuals with normal glucose tolerance (NGT) and newly diagnosed T2D. Fifty individuals with newly diagnosed T2D and 50 age-, sex-, BMI-matched individuals with NGT underwent liquid mixed-meal tolerance tests to measure glucagon and metabolites, hyperinsulinemic-euglycemic clamps with stable isotope dilution, indirect calorimetry to assess insulin sensitivity and lipid oxidation, and 1H/31P magnetic resonance spectroscopy and MRI to quantify HLC, ATP, and visceral adipose tissue (VAT) volume. Individuals with T2D had an ∼65% higher HLC as well as higher fasting and postprandial glucagonemia (∼30% and ∼75%) than those with NGT. Multivariable linear regression analyses revealed that the presence of MASLD, but not T2D, was associated with higher fasting glucagonemia. Interestingly, postprandial glucagon was related to HLC only in T2D, leading to ∼47% higher early postprandial glucagonemia in individuals with combined MASLD and T2D. These differential associations were independent of insulin sensitivity or VAT volume, and neither were mediated by amino acids or NEFAs. Hyperglucagonemia in the face of higher HLC in early T2D is not due to differences in insulin sensitivity or glucagonotropic metabolites but could suggest hepatic glucagon resistance.

To investigate previous gestational diabetes mellitus (GDM) as a potential risk factor for diabetic retinopathy (DR) in women with diabetes, including the potential role of GDM severity and hypertension after pregnancy. A nationwide, register-based cohort study including all women giving birth in Denmark in 1997-2018. We defined GDM and DR using ICD-10 codes. GDM severity was a proxy based on insulin treatment during GDM pregnancy. Subsequent diabetes and hypertension were based on ICD-10 codes and/or medication postpregnancy. Statistical analyses included Cox regression. The complete study population comprised 708,250 women. The GDM prevalence was 3.4%, and the overall median follow-up was 12 years. Diabetes developed subsequently in 18,556 women, and DR occurred in 655 of these. In the women who developed diabetes, previous GDM was associated with a threefold higher risk of DR (adjusted hazard ratio [aHR] 3.0 [95% CI 2.6-3.6]). The risk increased with increasing GDM severity (aHRs 5.6 [95% CI 4.5-6.9] and 2.4 [95% CI 2.0-2.9]) in women with previous GDM with and without insulin treatment, respectively, compared with women without previous GDM [reference group]). In women with subsequent hypertension, GDM exposure was associated with a 2.7-fold higher DR risk (aHR 2.7 [95% CI 2.1-3.5]). This large population-based study identified GDM as significant risk factor for DR in parous women with diabetes, a risk that increased with increasing GDM severity and postpregnancy hypertension development. On the basis of this study, planning of DR screening strategies should include awareness of GDM history.

Glycemic management metrics derived from continuous glucose monitoring (CGM) are increasingly recognized as important therapeutic targets. We performed one of the first comparisons of CGM metrics and achievement of CGM targets among four classes of glucose-lowering medications in combination with metformin. The Glycemia Reduction Approaches in Diabetes (GRADE) study randomly assigned participants with type 2 diabetes and taking metformin to add one of four glucose-lowering medications (insulin glargine, glimepiride, liraglutide, or sitagliptin) and followed them for glycemic outcomes for 5 ± 1.3 years. A 2-week masked CGM analysis was conducted midstudy in 1,080 participants to evaluate CGM metrics, 24-h ambulatory glucose profile, and achievement of consensus goals. Treatment effects among the four groups were compared. The sitagliptin and liraglutide groups had the highest time in range 70-180 mg/dL (TIR70-180) and the lowest time below range <70 mg/dL (TBR<70) and percentage coefficient of variation (%CV). The glimepiride group had the lowest TIR70-180, and the highest %CV, TBR<70, and number of CGM-derived hypoglycemic events (P < 0.001), and was the only drug showing daytime hypoglycemia. Sitagliptin and liraglutide were best for achieving consensus goals of very low TBR<54 <1% and the combined metric of TIR70-180 >70% and TBR<70 <4% (P < 0.001). When stratified by HbA1c, mean glucose did not differ among treatments, but %CV and TBR<70 were higher with glargine and glimepiride within each HbA1c stratum. Incretin class drugs had the lowest %CV, the least hypoglycemia, and best achievement of CGM-based glycemic targets. CGM metrics and profiles provide clinical insights, beyond HbA1c, to guide diabetes management.

Adult-onset type 1 diabetes is not well characterized, especially after 40 years of age, and is commonly misdiagnosed as type 2 diabetes. We evaluated the differences in clinical presentation, islet autoantibodies, and HLA genetics between pediatric- and adult-onset type 1 diabetes. Individuals who were newly diagnosed with type 1 diabetes were tested for islet autoantibodies within 1 year of diagnosis in this retrospective study. Islet autoantibodies against GAD, insulin, islet antigen 2, and zinc transporter 8 were measured using fluid-phase radiobinding assays. High-resolution HLA class I (n = 655) and II (n = 1,196) typing was performed in a subset of participants. In total, 414 adults (aged ≥20 years) and 2,000 children were included. Adults were aged 20 to 76 years and had a mean BMI of 23.5 ± 4.7 kg/m2 at onset. Compared with children, adults presented with diabetic ketoacidosis (DKA) less frequently (32.6% vs. 56.0%; P < 0.001) and with slightly lower HbA1c values (11.3% ± 2.6% vs. 12.0% ± 2.4%; P < 0.001). Notably, adults older than 40 years (n = 84) presented with DKA only 13.1% of the time. Adults more often presented with zero or one islet autoantibodies compared with children (43.0% vs. 20.2%; P < 0.001). There were no differences in high-risk HLA haplotypes between adults and children (DR4-DQ8: 57.1% vs. 63.7%; P = 0.060; DR3-DQ2: 43.6% vs. 46.1%; P = 0.482). Adult-onset type 1 diabetes is characterized by a reduced frequency of DKA and by fewer total islet autoantibodies. Our findings can help in the accurate diagnosis of type 1 diabetes in adults.

It has been postulated that pregnancies may contribute to the lifetime risk of type 2 diabetes mellitus (T2DM) in women, although direct evidence is lacking. In this context, we hypothesized that pregnancy may impact the long-term natural history of the pathophysiologic determinants of T2DM: insulin sensitivity and β-cell function. We sought to evaluate 10-year trajectories of these features in parous women with and without an additional pregnancy. Metabolic characterization was done in 303 women at 1 year postpartum and on three or more occasions over the decade thereafter. Each assessment included an oral glucose tolerance test, enabling serial evaluation of insulin sensitivity/resistance (Matsuda index; HOMA-insulin resistance [IR]), β-cell function (Insulin Secretion-Sensitivity Index-2; insulinogenic index/HOMA-IR), and glycemia. Linear mixed-effect models adjusted for diabetes risk factors were constructed to evaluate the natural time trend of these measures over 10 years in those with (n = 78) and without (n = 225) an additional pregnancy. At baseline, women who subsequently had an additional pregnancy were younger (P < 0.001) and more likely to be primiparous (P < 0.001) than their peers. Notably, they had higher covariate-adjusted insulin sensitivity (Matsuda index) at baseline (estimated adjusted average difference 1.64; 95% CI 0.22-2.86) and at 1.5 years' follow-up (1.28; -0.15 to 2.50), but this difference disappeared by 3.5 years and 5.5 years. The 10-year trajectory of the Matsuda index differed between the groups (time-group interaction P = 0.02), with no differences in trajectories of β-cell function and glycemia. Pregnancy is associated with worsening of the long-term trajectory of insulin sensitivity, revealing both a pathophysiologic basis for enhanced diabetes risk and a target for risk modification.

Variations of disease patterns among populations, geographies, and time periods underpin the use of descriptive and analytical cohort analysis to define causal relationships between exposures and outcomes. This epidemiological knowledge forms the basis for designing clinical experiments to inform practice and policies. In the 1990s, rapid environmental and lifestyle changes among Chinese living in Hong Kong led to a rising prevalence of diabetes. The benefits of structured care in a clinical trial setting motivated the establishment of the Hong Kong Diabetes Register (HKDR) in 1995 as a data-driven quality improvement program accompanied by a biobank. Systematic data collection and analysis revealed the Asian diabetes phenotype characterized by young age at diagnosis, moderately increased BMI, visceral fat excess, and propensity for chronic kidney disease. In 2000, the HKDR protocol was incorporated into the territory-wide electronic medical record (EMR) system with setup of diabetes centers/teams for implementation. This 2-yearly Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) contributed to marked decline in diabetes-related complication and death rates. In 2007, the HKDR and its equations were digitalized to become the first web-based Joint Asia Diabetes Evaluation (JADE) platform for risk stratification and personalized reporting with decision support aimed at closing care gaps in Asia. The HKDR with its multidimensional data provides the fulcrum for building capacity to transform care and discover knowledge, including on the vulnerability, multiple hits, and reduced capacity of β-cells underlying young-onset diabetes. Using well-designed registers and biobanks to redefine diabetes can lead to innovative diabetes prediction, prevention, classification, and treatment with value, quality, and precision.

To examine the association between fiber from various food sources and type 2 diabetes (T2D) risk, as well as the molecular profiles involved. Using data from three large prospective U.S. cohorts comprising 195,222 participants observed for up to 34 years, we evaluated the association between fiber from various food sources and T2D risk. We also assessed the association between fiber intake, plasma metabolic biomarkers, and a metabolomic profile indicative of T2D risk. Additionally, we examined gut microbial features related to fiber intake and the T2D metabolomic profile. During follow-up, we documented 18,369 incident T2D cases. Higher intakes of total fiber (hazard ratio [HR] comparing extreme quintiles 0.88; 95% CI 0.82, 0.94), cereal fiber (HR 0.77; 95% CI 0.73, 0.82), and fruit fiber (HR 0.82; 95% CI 0.78, 0.87) were each associated with a lower T2D risk. Greater intakes of total fiber, cereal fiber, and fruit fiber, but not vegetable fiber, were linked to more favorable plasma profiles of insulinemic, lipid, and inflammatory biomarkers and a metabolomic profile indicative of a lower T2D risk. We also identified multiple gut microbial species, such as Faecalibacterium prausnitzii, Ruminococcus lactaris, and Gemmiger formicilis, along with relevant butyric acid-producing enzymes, all of which were associated with higher fruit fiber intake and a metabolomic profile indicating a lower likelihood of T2D development. Higher intakes of total, cereal, and fruit fiber are associated with a lower risk of T2D and a more favorable metabolic profile, with the gut microbiome potentially contributing to the beneficial association of fruit fiber.