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In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes 1 . Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies. In Greenlandic Inuit, a TBC1D4 loss-of-function mutation increases type 2 diabetes risk by tenfold. Carriers show severe muscle insulin resistance, impaired glucose disposal and reduced muscle GLUT4, yet exercise mitigates these defects, offering potential for personalized lifestyle interventions.

Diabetic foot ulcers are a frequent and serious complication of diabetes with a high risk of amputation. Exercise has been shown to promote wound healing; however, patients with non-healing foot ulcers have limited ability to exercise due to the foot ulcer. Other strategies are therefore warranted. We evaluated the effect of eight weeks of two-leg passive movement exercise on wound healing in patients with non-healing diabetic foot ulcers. Twenty-one patients were included in the study and randomized into either a control or a passive movement exercise intervention group. The primary outcome measure was the wound area. Sixteen participants completed the trial. Wound sizes for the passive movement intervention group were 274 mm and 58 mm at baseline and week 8, compared to 148 mm (p=0.31) and 136 mm (p=0.51) in the control group (week 16; 7 mm vs. 23 mm , p=0.55). The mean wound area percentual reduction between baseline and week 8 was higher in the intervention group (76% vs. 36%, difference 40%, p=0.062). The two-leg passive movement intervention showed a non-significant difference in wound healing and was well tolerated by patients with diabetic foot ulcers. Although the study shows potential, the results should be interpreted with its limitations of being underpowered and potentially confounded. We encourage larger randomized controlled trials to be conducted, to elucidate whether the two-leg passive movement intervention can be used to accelerate wound healing in non-healing ulcers.

Obesity-related glomerulopathy and diabetic nephropathy (DN) are serious complications to metabolic syndrome and diabetes. The purpose was to study effects of a fat, fructose and cholesterol-rich (FFC) diet with and without salt in order to induce hypertension on kidney function and morphology in Göttingen Minipigs with and without diabetes. Male Göttingen Minipigs were divided into 4 groups: SD (standard diet, n = 8), FFC (FFC diet, n = 16), FFC-DIA (FFC diet + diabetes, n = 14), FFC-DIA + S (FFC diet with extra salt + diabetes, n = 14). Blood and urine biomarkers, glomerular filtration rate (GFR), blood pressure (BP) and resistive index (RI) were evaluated after 6–7 months (T1) and 12–13 months (T2). Histology, electron microscopy and gene expression (excluding FFC-DIA + S) were evaluated at T2. All groups fed FFC-diet displayed obesity, increased GFR and RI, glomerulomegaly, mesangial expansion (ME) and glomerular basement membrane (GBM) thickening. Diabetes on top of FFC diet led to increased plasma glucose and urea and proteinuria and tended to exacerbate the glomerulomegaly, ME and GBM thickening. Four genes (CDKN1A, NPHS2, ACE, SLC2A1) were significantly deregulated in FFC and/or FFC-DIA compared to SD. No effects on BP were observed. Göttingen Minipigs fed FFC diet displayed some of the renal early changes seen in human obesity. Presence of diabetes on top of FFC diet exacerbated the findings and lead to changes resembling the early phases of human DN.

Understanding the environmental and microbial processes involved in DNA degradation from archaeological remains is a fundamental part of managing bone specimens. We investigated the state of DNA preservation in 33 archaeozoological caribou ( Rangifer tarandus ) ribs excavated from the same excavation trench at a former Inuit hunting camp in West Greenland, separated by 43 years: 1978 and 2021. Our findings show that DNA is better preserved in the most recently excavated samples, indicating a detrimental effect of museum storage on DNA integrity. Additionally, our data reveals a diverse microbiome in these bones, encoding genes relevant for bone degradation, such as enzymatic families relating to collagenases, peptidases and glycosidases. Microbes associated with bone degradation were present in both new and historical samples, with museum-stored bones showing significantly more DNA damage. Overall, our research sheds light on the nuanced dynamics governing the preservation of genomic material in archaeological contexts, underscoring the vital importance of careful considerations in museum curation practices for the sustainable conservation of invaluable skeletal records in museum repositories and in situ. DNA preservation in archaeozoological caribou ribs from West Greenland Inuit hunting camp shows better quality in newly excavated samples, revealing detrimental effects of museum storage and diverse microbial communities involved in bone degradation.