Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

Low-carb and ketogenic diets are popular among clinicians and patients, but the appropriateness of reducing carbohydrates intake in obese patients and in patients with diabetes is still debated. Studies in the literature are indeed controversial, possibly because these diets are generally poorly defined; this, together with the intrinsic complexity of dietary interventions, makes it difficult to compare results from different studies. Despite the evidence that reducing carbohydrates intake lowers body weight and, in patients with type 2 diabetes, improves glucose control, few data are available about sustainability, safety and efficacy in the long-term. In this review we explored the possible role of low-carb and ketogenic diets in the pathogenesis and management of type 2 diabetes and obesity. Furthermore, we also reviewed evidence of carbohydrates restriction in both pathogenesis of type 1 diabetes, through gut microbiota modification, and treatment of type 1 diabetes, addressing the legitimate concerns about the use of such diets in patients who are ketosis-prone and often have not completed their growth.

OBJECTIVEFew studies have assessed the efficacy of carbohydrate counting in type 1 diabetes, and none have validated its efficacy in patients who are treated with continuous subcutaneous insulin infusion (CSII). The aim of our study was to test the effect of carbohydrate counting on glycemic control and quality of life in adult patients with type 1 diabetes who are receiving CSII.RESEARCH DESIGN AND METHODSSixty-one adult patients with type 1 diabetes treated with CSII were randomly assigned to either learning carbohydrate counting (intervention) or estimating pre-meal insulin dose in the usual empirical way (control). At baseline and 12 and 24 weeks, we measured HbA1c, fasting plasma glucose, BMI, waist circumference, recorded daily insulin dose, and capillary glucose data, and administered the Diabetes-Specific Quality-of-Life Scale (DSQOLS) questionnaire.RESULTSIntention-to-treat analysis showed improvement of the DSQOLS score related to diet restrictions (week 24 – baseline difference, P = 0.008) and reduction of BMI (P = 0.003) and waist circumference (P = 0.002) in the intervention group compared with control subjects. No changes in HbA1c, fasting plasma glucose, daily insulin dose, and hypoglycemic episodes (<2.8 mmol/L) were observed. Per-protocol analysis, including only patients who continuously used carbohydrate counting and CSII during the study, confirmed improvement of the DSQOLS score and reduction of BMI and waist circumference, and showed a significant reduction of HbA1c (−0.35% vs. control subjects, P = 0.05).CONCLUSIONSAmong adult patients with type 1 diabetes treated with CSII, carbohydrate counting is safe and improves quality of life, reduces BMI and waist circumference, and, in per-protocol analysis, reduces HbA1c.

This study shows that duodenal mucosa in T1D presents disease-specific abnormalities in the inflammatory profile and microbiota. Understanding the mechanisms underlying these features is critical to disentangle the complex pathogenesis of T1D and to gain new perspectives for future therapies targeting the intestine.

OBJECTIVEThe gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3+ regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3+ Treg cells.RESEARCH DESIGN AND METHODSWe collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4+ and CD8+ T cells, NK cells, γδ T cells, CD103+CD11c+ LPDCs, and CD4+CD25+FoxP3+CD127− Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3+ Treg cells) by LPDCs of T1D patients and control subjects.RESULTSOur analysis revealed a significant reduction in the percentage of intestinal CD4+CD25+FoxP3+CD127− Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4+CD25− T cells into CD4+CD25+FoxP3+CD127− Treg cells.CONCLUSIONSOur data indicate that T1D patients have a reduced number of intestinal FoxP3+ Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic β-cells and preventing T1D.

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A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19–related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1 + T cells, as compared with healthy controls. Plasma levels of IL-1 β , IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1 -targeting miR–15-5p, in CD8 + T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post–COVID-19 immune abnormalities; indeed, we also noted an increased T cell–mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post–COVID-19 immune abnormalities and stimulates an anti–SARS-CoV-2 immune response.

Recent studies have shown that SARS-CoV-2 infection may induce metabolic distress, leading to hyperglycemia in patients affected by COVID-19. We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. While there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which can be abrogated by the use of anti-IL1β, anti-IL-6 and anti-TNF-α, cytokines known to be highly upregulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evident in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19, revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, were detected in post-mortem pancreatic tissues, suggestive of β-cell altered proinsulin processing, as well as β-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islets function and survival by creating inflammatory conditions and possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19.