In This Issue of Diabetes Open Access

Transplantation of pancreatic stem cells may offer a way of restoring β-cell function in those with type 1 diabetes, and trials are currently underway to assess the efficacy of this process. However, Bruin et al. (p. 1297) warn in this issue of Diabetes that the presence of thyroid disease (common in individuals with type 1 diabetes)—and specifically hypothyroidism—may result in implanted pancreatic progenitor cells differentiating towards α- and ε-cell lineages at the expense of β-cell formation and therefore potentially reduced insulin secretion. To assess the risks more fully the authors induced hypo- or hyperthyroidism in mice and compared the groups to mice with euthyroidism (the control). All of the mice then received an implant of pancreatic progenitor cells in the form of an encapsulated insert. Hyperthyroidism made no major difference to differentiation of the progenitor cells in comparison to the control in that intended graft function was minimally affected. Hypothyroidism on the other hand made a big difference. Acute hypothyroidism transiently impaired human C-peptide secretion while chronic hypothyroidism severely blunted C-peptide secretion. On top of that, chronic hypothyroidism resulted in impaired glucose-stimulated insulin secretion and elevated plasma glucagon levels. When explaining this, the authors found that the grafts in these mice contained fewer β-cells and increased glucagon and ghrelin⁺ cells. This pointed them to conclude that the long-term thyroid hormone deficiency likely results in differentiation of the pancreatic progenitor cells away from β-cell formation. Their warning is straightforward regarding the ongoing trials of such stem cell transplants: “…that eligible [type 1 diabetes] patients are screened for thyroid dysfunction and treated accordingly to reduce the risk of off-target cell differentiation leading to compromised graft function.” Commenting more specifically, author Timothy J. Kieffer stated: “Our findings point to the need to better assess how patient variables might impact the development and function of transplanted stem cell–derived pancreatic progenitor cells and perhaps that it may be preferable to differentiate cells further toward mature islet cells prior to transplant such that they are less susceptible to the formation of off-target cells.”

Bruin et al. Hypothyroidism impairs human stem cell–derived pancreatic progenitor cell maturation in mice. Diabetes 2016;65:1297–1309

Brown adipose tissue (BAT) can convert glucose into heat directly and according to the report by Hanssen et al. (p. 1179) in this issue of Diabetes, this process can be enhanced significantly in obese subjects through exposure to cold. The study focused on 10 metabolically healthy but obese males, exposing them to a 10-day cold acclimation period. Then, using positron emission tomography (PET) scans and the tracer [¹⁸F]fluorodeoxyglucose, the researchers measured BAT activity and specifically glucose uptake into the cells. In addition to the recruitment of BAT, cold also induced translocation of GLUT4 to the sarcoma (the membrane) of muscle cells to facilitate glucose uptake. BAT activity was also negatively related to age in that younger subjects (<40 years of age, n = 6) had increased BAT activity while older subjects did not. Expanding on this particular finding, author Wouter D. van Marken Lichtenbelt said: “We found it interesting that, although levels of BAT before acclimation were significantly lower in obese subjects, the levels of BAT in the younger subjects after cold acclimation were comparable to the levels of healthy lean subjects. Although these observations need to be confirmed in larger groups, this may indicate that the capacity to recruit BAT at a young age is not hampered by obesity per se.” More widely, he pointed out: “The broader implications of the study may be the therapeutic value. We need more information about the long-term effects and the length and intensity of cold exposure itself. This information will reveal whether mild cold exposure can be implemented in the daily living environment or alternatively as more intense cold in short-term therapy sessions. It is also important to determine the extent that body weight can be affected, and importantly to what extent a more healthy metabolic profile can be attained by cold acclimation. It could be that it is not only cold, but the variation in environmental temperature that can have health effects. These aspects will be studied in the near future.”

Hanssen et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 2016;65:1179–1189

Exercise stimulates the AMP-activated protein kinase (AMPK) signaling network, which in turn drives glucose uptake into skeletal muscle, and according to Kjøbsted et al. (p. 1219) this process is likely not compromised in patients with type 2 diabetes after all. Previously, AMPK and downstream targets were thought to be intolerant to exercise in patients with type 2 diabetes, suggesting that this might lead to muscle insulin resistance. To unravel the effects of exercise on AMPK signaling, the authors examined muscle biopsy samples obtained from age- and weight-matched overweight/obese patients with type 2 diabetes (n = 13) or without type 2 diabetes (n = 14, controls). Biopsies were taken before, immediately after, and 3 h after exercise, and then assayed for a range of targets in the network. While noting that exercise affected the activity of individual components of the network in different ways and at different time points, there was no difference between the effects seen in the patients with type 2 diabetes or control subjects. Commenting more widely on the study, Jørgen F.P. Wojtaszewski said: “The observations in our study are quite important for our thinking of AMPK as a potential drug target in type 2 diabetes. At least in the cohorts we have studied so far, the network is fully intact in skeletal muscle. In addition, a key regulator of mitochondria biogenesis, PGC-1α, is also normally regulated during recovery from exercise. So from these data we would expect that skeletal muscle in subjects with type 2 diabetes would adapt normally to acute exercise and exercise training. Our study suggests that targeting the network to improve metabolic control is indeed feasible in patients with type 2 diabetes—and this could be by physical activity or by pharmacological intervention. Whether our observations relate to all patients with type 2 diabetes is not clear. The possibility exists that, as the disease progresses and metabolic control becomes severely affected, muscle integrity and the ability to adapt normally also becomes compromised.”

Kjøbsted et al. Intact regulation of the AMPK signaling network in response to exercise and insulin in skeletal muscle of male patients with type 2 diabetes: illumination of AMPK activation in recovery from exercise. Diabetes 2016;65:1219–1230

Distinct profiles of insulitis are likely to exist and may determine the extent of pancreatic β-cell destruction in type 1 diabetes. Moreover, Leete et al. (p. 1362) report that the insulitis profile is likely to influence the age at onset of type 1 diabetes. The authors, reporting an extension of an earlier analysis, show that two insulitis profiles may exist in terms of the proportions of infiltrating CD20⁺ β-cells (CD20Hi and CD20Lo). While present in the U.K. cohort studied previously, the profiles also appear to exist in equivalent samples obtained in the U.S. and Norway. Based mainly on pancreas samples recovered postmortem from patients with very recent-onset type 1 diabetes, the study used a variety of immunohistochemisty approaches and imaging to quantify a series of leukocytes involved in the process of insulitis. Among those studied, the researchers show that patients receiving a diagnosis before 7 years of age display the CD20Hi profile. Patients receiving a diagnosis after 13 years of age conversely always had a CD20Lo profile. Patients between these ages were equally likely to have either profile. Crucially the researchers then show that the proportion of insulin-containing islets remaining at diagnosis increases with age. According to the authors, patients receiving a diagnosis in or beyond their teenage years may retain ∼40% of islets that can produce insulin. This, they report, may be important as it implies that a functional deficit rather than complete β-cell destruction may exist in such patients. According to the authors, the outcome may have important consequences for the interpretation of earlier trials of immunotherapeutics and indeed the design of future studies of potential interventions in this area. According to authors Noel G. Morgan and Sarah J. Richardson: “Our results suggest that strategies designed to reduce islet inflammation, while also promoting β-cell function, may be of value in many patients with type 1 diabetes.”

Leete et al. Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes 2016;65:1362–1369