Background

In addition to peripheral neuropathy of various kinds, diabetes can also cause central neuropathy, which among other things can manifest itself as premature cognitive dysfunction, often linked to vascular dysfunction. Although the link between diabetes and cognitive dysfunction was discovered more than 100 years ago and has important clinical implications, this diabetes complication remains relatively unknown. Recent years have seen research that has clarified cerebral insulin resistance and defective insulin signaling as examples of pathogenic factors behind this cognitive impairment in diabetes.

Method

We provide a narrative review of select and contemporary publications with relevance for the interface between diabetes/prediabetes and cognitive function.

Results

Recently published studies show that physical activity can reverse insulin resistance in the brain as well as cognitive impairment and pathological appetite regulation. Pharmacological interventions with, for example, nasal insulin, GLP-1 receptor agonists, SGLT-2 inhibitors, or PPAR-γ agonists have also shown promising results.

Conclusion

Optimization of lifestyle factors (e.g. physical activity), as well as several pharmaceutical agents already in clinical use against diabetes, have shown promising results in improving cognitive function in diabetic patients. An important task for primary health care, where most patients with type 2 diabetes are diagnosed, treated, and followed, is to increase awareness and early detection of cognitive dysfunction in these patients for optimizing risk factor control.

We report a case of new-onset, nonautoimmune, nonketotic, and noninsulinopenic type 2-like diabetes in a previously normoglycemic middle-aged man debuting after vaccination against COVID-19. This was not a mild or short-lived glucose intolerance, but severe and long-standing hyperglycemia with a high glycated hemoglobin level. However, the course of the diabetes was highly atypical and surprising in that it spontaneously disappeared after a few months and did not recur despite the patient being off all antidiabetic drugs for several months and without any changes in body weight or lifestyle. The mechanisms by which severe diabetes unfolded and later remitted in this patient remain elusive. Nonetheless, and notwithstanding whether or not there was a cause-and-effect relation between the vaccinations and his diabetes, the highly atypical course of spontaneously remitting nonautoimmune diabetes lends itself to mechanistic efforts aimed at understanding the biology and pathophysiology of insulin-producing β cells in health and disease. This case report should not be construed as vaccine skepticism or deter anyone, especially with diabetes/obesity, from vaccination against COVID-19. However, it calls for increased vigilance among health care providers for unusual and unexpected metabolic effects of COVID-19 and its vaccines.

A 29-year-old man was admitted to the hospital in a state of reduced consciousness with new-onset diabetes and positive for coronavirus disease 2019. He presented with severe ketoacidosis and profound hypokalemia. While his diabetic ketoacidosis was promptly corrected, it proved extremely difficult to maintain normokalemia. For a total of 49 hours, not less than 1127 mmol of i.v. Addex-potassium (potassium hydroxide and dipotassium phosphate trihydrate; ∼ 25 mmol/hour) in addition to 76 mmol/d of oral potassium was required, ie, tantamount to doses used to achieve cardioplegia. Severe, sustained, treatment-resistant and potentially lethal hypokalemia may thus occur in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and should be actively monitored. Based upon these findings and converging evidence in the literature, we propose a model in which disruption of angiotensin-converting enzyme 2 by SARS-CoV-2 activates the angiotensin-II pathway, thereby enhancing aldosterone production. Excess aldosterone activates renal epithelial sodium channels, thus promoting massive loss of potassium through urinary excretion. This implies that severe hypokalemia by SARS-CoV-2 infection may be amenable to treatment with potassium-sparing drugs antagonizing the aldosterone receptor, such as spironolactone or eplerenone, whereas potassium supplementation even in very high doses may be futile.

Androgen secretion by testicular germ-cell tumors (GCTs) appears to be markedly rare and likely underreported in the literature. This case study highlights a patient with such a rare tumor, underscoring a notable and yet easily avoidable diagnostic oversight in one of the most prevalent cancers among men. We advocate for increased vigilance and the inclusion of specific symptomatic screening for hyperandrogenism of select patients in existing guidelines and, where appropriate, the implementation of standardized hormonal laboratory analyses in both pre- and post-orchidectomy assessments. These measures could enhance the reporting of cases, standardize care, and improve understanding of the underlying mechanisms of these rare tumors. Finally, future studies should explore the implications of androgen secretion for the prognosis and treatment of GCTs.

The prevalence of type 2 diabetes (T2D) is increasing relentlessly all over the world, in parallel with a similar increase in obesity, and is striking ever younger patients. Only a minority of patients with T2D attain glycemic targets, indicating a clear need for novel antidiabetic drugs that not only control glycemia but also halt or slow the progressive loss of β-cells. Two entirely novel classes of antidiabetic agents-glucokinase activators and imeglimin-have recently been approved and will be the subject of this review.Allosteric activators of glucokinase, an enzyme stimulating insulin secretion in β-cells and suppressing hepatic glucose production, are oral low-molecular-weight drugs. One of these, dorzagliatin, is approved in China for use in adult patients with T2D, either as monotherapy or as an add-on to metformin. It remains to be seen whether the drug will produce sustained antidiabetic effects over many years and whether the side effects that led to the discontinuation of early drug candidates will limit the usefulness of dorzagliatin.Imeglimin-which shares structural similarities with metformin-targets mitochondrial dysfunction and was approved in Japan against T2D. In preclinical studies, the drug has also shown promising β-cell protective and preservative effects that may translate into disease-modifying effects.Hopefully, these two newcomers will contribute to filling the great medical need for new treatment modalities, preferably with disease-modifying potential. It remains to be seen where they will fit in contemporary treatment algorithms, which combinations of drugs are effective and which should be avoided. Time will tell to what extent these new antidiabetic agents will add value to the current treatment options against T2D in terms of sustained antidiabetic effect, acceptable safety, utility in combination therapy, and impact on hard end-points such as cardiovascular disease.

Diabetes classification is not as defined as it used to be. A patient with one type of diabetes can have diagnostic criteria of another type, which may affect the course of the disease. Clinicians need to consider that when dealing with patients who do not fit the exact description of their diagnosed type of diabetes.